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  • 1.
    Abdelwahab, Mahmoud Tareq
    et al.
    Univ Cape Town, Dept Med, Div Clin Pharmacol, Cape Town, South Africa..
    Court, Richard
    Univ Cape Town, Dept Med, Div Clin Pharmacol, Cape Town, South Africa..
    Everitt, Daniel
    Global Alliance TB Drug Dev, New York, NY USA..
    Diacon, Andreas H.
    Stellenbosch Univ, Dept Med, Tygerberg, South Africa.;Task Appl Sci, Bellville, South Africa..
    Dawson, Rodney
    Univ Cape Town, Div Pulmonol, Lung Inst, Cape Town, South Africa.;Univ Cape Town, Dept Med, Lung Inst, Cape Town, South Africa..
    Svensson, Elin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Radboud Univ Nijmegen, Radboud Inst Hlth Sci, Dept Pharm, Med Ctr, Nijmegen, Netherlands.;Uppsala Univ, Dept Pharm, Uppsala, Sweden..
    Maartens, Gary
    Univ Cape Town, Dept Med, Div Clin Pharmacol, Cape Town, South Africa.;Univ Cape Town, Wellcome Ctr Infect Dis Res Africa, Inst Infect Dis & Mol Med, Cape Town, South Africa..
    Denti, Paolo
    Univ Cape Town, Dept Med, Div Clin Pharmacol, Cape Town, South Africa..
    Effect of Clofazimine Concentration on QT Prolongation in Patients Treated for Tuberculosis2021In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 65, no 7, article id e02687-20Article in journal (Refereed)
    Abstract [en]

    Clofazimine is classified as a WHO group B drug for the treatment of rifampin-resistant tuberculosis. QT prolongation, which is associated with fatal cardiac arrhythmias, is caused by several antitubercular drugs, including clofazimine, but there are no data quantifying the effect of clofazimine concentration on QT prolongation. Our objective was to describe the effect of clofazimine exposure on QT prolongation. Fifteen adults drug-susceptible tuberculosis patients received clofazimine monotherapy as 300mg daily for 3 days, followed by 100mg daily in one arm of a 2-week, multiarm early bactericidal activity trial in South Africa. Pretreatment Fridericia-corrected QT (QTcF) (105 patients, 524 electrocardiograms [ECGs]) and QTcFs from the clofazimine monotherapy arm matched with clofazimine plasma concentrations (199 ECGs) were interpreted with a nonlinear mixed-effects model. Clofazimine was associated with significant QT prolongation described by a maximum effect (Emax) function. We predicted clofazimine exposures using 100-mg daily doses and 2 weeks of loading with 200 and 300mg daily, respectively. The expected proportions of patients with QTcF change from baseline above 30 ms (DQTcF. 30) were 2.52%, 11.6%, and 23.0% for 100-, 200-, and 300-mg daily doses, respectively. At steady state, the expected proportion with Delta QTcF of >30 ms was 23.7% and with absolute QTcF of >450 ms was 3.42% for all simulated regimens. The use of loading doses of 200 and 300mg is not predicted to expose patients to an increased risk of QT prolongation, compared with the current standard treatment, and is, therefore, an alternative option for more quickly achieving therapeutic concentrations.

  • 2.
    Abdelwahab, Mahmoud Tareq
    et al.
    Univ Cape Town, Dept Med, Div Clin Pharmacol, Cape Town, South Africa..
    Wasserman, Sean
    Univ Cape Town, Dept Med, Div Infect Dis & HIV Med, Cape Town, South Africa.;Univ Cape Town, Wellcome Ctr Infect Dis Res Africa, Inst Infect Dis & Mol Med, Cape Town, South Africa..
    Brust, James C. M.
    Albert Einstein Coll Med, Div Gen Internal Med, New York, NY USA.;Albert Einstein Coll Med, Div Infect Dis, New York, NY USA..
    Gandhi, Neel R.
    Emory Univ, Rollins Sch Publ Hlth, Dept Epidemiol, Atlanta, GA USA.;Emory Univ, Rollins Sch Publ Hlth, Dept Global Hlth, Atlanta, GA 30322 USA.;Emory Univ, Emory Sch Med, Dept Med Infect Dis, Atlanta, GA USA..
    Meintjes, Graeme
    Univ Cape Town, Dept Med, Div Infect Dis & HIV Med, Cape Town, South Africa.;Univ Cape Town, Wellcome Ctr Infect Dis Res Africa, Inst Infect Dis & Mol Med, Cape Town, South Africa..
    Everitt, Daniel
    Global Alliance TB Drug Dev, New York, NY USA..
    Diacon, Andreas
    Task Appl Sci, Bellville, South Africa.;Stellenbosch Univ, Dept Med, Cape Town, South Africa..
    Dawson, Rodney
    Univ Cape Town, Lung Inst, Cape Town, South Africa.;Univ Cape Town, Div Pulmonol, Dept Med, Cape Town, South Africa..
    Wiesner, Lubbe
    Univ Cape Town, Dept Med, Div Clin Pharmacol, Cape Town, South Africa..
    Svensson, Elin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Radboud Univ Nijmegen, Radboud Inst Hlth Sci, Dept Pharm, Med Ctr, Nijmegen, Netherlands.
    Maartens, Gary
    Univ Cape Town, Dept Med, Div Clin Pharmacol, Cape Town, South Africa.;Univ Cape Town, Wellcome Ctr Infect Dis Res Africa, Inst Infect Dis & Mol Med, Cape Town, South Africa..
    Denti, Paolo
    Univ Cape Town, Dept Med, Div Clin Pharmacol, Cape Town, South Africa..
    Clofazimine pharmacokinetics in patients with TB: dosing implications2020In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 75, no 11, p. 3269-3277Article in journal (Refereed)
    Abstract [en]

    Background: Clofazimine is in widespread use as a key component of drug-resistant TB regimens, but the recommended dose is not evidence based. Pharmacokinetic data from relevant patient populations are needed to inform dose optimization. Objectives: To determine clofazimine exposure, evaluate covariate effects on variability, and simulate exposures for different dosing strategies in South African TB patients. Patients and methods: Clinical and pharmacokinetic data were obtained from participants with pulmonary TB enrolled in two studies with intensive and sparse sampling for up to 6 months. Plasma concentrations were measured by LC-MS/MS and interpreted with non-Linear mixed-effects modelling. Body size descriptors and other potential covariates were tested on pharmacokinetic parameters. We simulated different dosing regimens to safely shorten time to average daily concentration above a putative target concentration of 0.25 mg/L. Results: We analysed 1570 clofazimine concentrations from 139 participants; 79 (57%) had drug-resistant TB and 54 (39%) were HIV infected. Clofazimine pharmacokinetics were well characterized by a three-compartment model. Clearance was 11.5 L/h and peripheral volume 10500 L for a typical participant. Lower plasma exposures were observed in women during the first few months of treatment, explained by higher body fat fraction. Model-based simulations estimated that a Loading dose of 200 mg daily for 2 weeks would achieve average daily concentrations above a target efficacy concentration 37 days earlier in a typical TB participant. Conclusions: Clofazimine was widely distributed with a Long elimination half-Life. Disposition was strongly influenced by body fat content, with potential dosing implications for women with TB.

  • 3.
    Abulfathi, Ahmed A.
    et al.
    Stellenbosch Univ, Fac Med & Hlth Sci, Dept Med, Div Clin Pharmacol, Cape Town, South Africa..
    Assawasuwannakit, Piyanan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Donald, Peter R.
    Stellenbosch Univ, Fac Med & Hlth Sci, Dept Paediat & Child Hlth, Desmond Tutu TB Ctr, Cape Town, South Africa..
    Diacon, Andreas H.
    Task Appl Sci, Bellville, South Africa.;Stellenbosch Univ, Fac Med & Hlth Sci, Dept Med, Cape Town, South Africa..
    Reuter, Helmuth
    Stellenbosch Univ, Fac Med & Hlth Sci, Dept Med, Div Clin Pharmacol, Cape Town, South Africa..
    Svensson, Elin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Radboud Univ Nijmegen, Med Ctr, Radboud Inst Hlth Sci, Dept Pharm, Nijmegen, Netherlands..
    Probability of mycobactericidal activity of para-aminosalicylic acid with novel dosing regimens2020In: European Journal of Clinical Pharmacology, ISSN 0031-6970, E-ISSN 1432-1041, Vol. 76, no 11, p. 1557-1565Article in journal (Refereed)
    Abstract [en]

    Purpose Para-aminosalicylic acid (PAS) is currently one of the add-on group C medicines recommended by the World Health Organization for multidrug-resistant tuberculosis treatment. At the recommended doses (8-12 g per day in two to three divided doses) of the widely available slow-release PAS formulation, studies suggest PAS exposures are lower than those reached with older PAS salt formulations and do not generate bactericidal activity. Understanding the PASER dose-exposure-response relationship is crucial for dose optimization. The objective of our study was to establish a representative population pharmacokinetics model for PASER and evaluate the probability of bactericidal and bacteriostatic target attainment with different dosing regimens.

    Methods To this end, we validated and optimized a previously published population pharmacokinetic model on an extended dataset. The probability of target attainment was evaluated for once-daily doses of 12 g, 14 g, 16 g and 20 g PASER.

    Results The final optimized model included the addition of variability in bioavailability and allometric scaling with body weight on disposition parameters. Peak PAS concentrations over minimum inhibitory concentration of 100, which is required for bactericidal activity are achieved in 53%, 65%, 72% and 84% of patients administered 12, 14, 16 and 20 g once-daily PASER, respectively, when MIC is 1 mg/L. For the typical individual, the exposure remained above 1 mg/L for >= 98% of the dosing interval in all the evaluated PASER regimens.

    Conclusion The pharmacokinetic/pharmacodynamic parameters linked to bactericidal activity should be determined for 14 g, 16 g and 20 g once-daily doses of PASER.

  • 4.
    Abulfathi, Ahmed A.
    et al.
    Univ Florida, Ctr Pharmacometr & Syst Pharmacol, Dept Pharmaceut, Orlando, FL 32827 USA.;Univ Maiduguri, Coll Med Sci, Dept Clin Pharmacol & Therapeut, Maiduguri, Nigeria.;Stellenbosch Univ, Fac Med & Hlth Sci, Dept Med, Div Clin Pharmacol, Cape Town, South Africa..
    Chaba, Linda A.
    Strathmore Univ, Strathmore Inst Math Sci, Nairobi, Kenya..
    Svensson, Elin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Radboud Univ Nijmegen Med Ctr, Radboud Inst Hlth Sci, Dept Pharm, Nijmegen, Netherlands..
    Pillai, Goonaseelan C.
    Univ Cape Town, Fac Hlth Sci, Dept Med, Div Clin Pharmacol, Cape Town, South Africa..
    Rosenkranz, Bernd
    Stellenbosch Univ, Fac Med & Hlth Sci, Dept Med, Div Clin Pharmacol, Cape Town, South Africa.;Fundisa African Acad Med Dev Cape Town, Cape Town, South Africa..
    Pharmacometrics - tools to assure optimal medicine use in low- and middle-income countries: Editorial2022In: Frontiers in Pharmacology, E-ISSN 1663-9812, Vol. 13, article id 1034807Article in journal (Other academic)
    Download full text (pdf)
    FULLTEXT01
  • 5.
    Abulfathi, Ahmed A.
    et al.
    Stellenbosch Univ, Fac Med & Hlth Sci, Dept Med, Div Clin Pharmacol, Stellenbosch, South Africa.;Univ Maiduguri, Coll Med Sci, Dept Clin Pharmacol & Therapeut, Maiduguri, Nigeria..
    de Jager, Veronique
    Task Appl Sci, Bellville, South Africa..
    van Brakel, Elana
    Task Appl Sci, Bellville, South Africa..
    Reuter, Helmuth
    Stellenbosch Univ, Fac Med & Hlth Sci, Dept Med, Div Clin Pharmacol, Stellenbosch, South Africa..
    Gupte, Nikhil
    Johns Hopkins Univ, Dept Med, Ctr TB Res, Baltimore, MD USA..
    Vanker, Naadira
    Task Appl Sci, Bellville, South Africa..
    Barnes, Grace L.
    Johns Hopkins Univ, Dept Med, Ctr TB Res, Baltimore, MD USA..
    Nuermberger, Eric
    Johns Hopkins Univ, Dept Med, Ctr TB Res, Baltimore, MD USA..
    Dorman, Susan E.
    Med Univ South Carolina, Dept Med, Charleston, SC USA..
    Diacon, Andreas H.
    Task Appl Sci, Bellville, South Africa.;Stellenbosch Univ, Fac Med & Hlth Sci, Dept Med, Stellenbosch, South Africa..
    Dooley, Kelly E.
    Johns Hopkins Univ, Div Clin Pharmacol, Dept Med, Ctr TB Res, Baltimore, MD USA.;Johns Hopkins Univ, Div Infect Dis, Dept Med, Ctr TB Res, Baltimore, MD USA..
    Svensson, Elin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Radboud Univ Nijmegen, Radboud Inst Hlth Sci, Dept Pharm, Med Ctr, Nijmegen, Netherlands..
    The Population Pharmacokinetics of Meropenem in Adult Patients With Rifampicin-Sensitive Pulmonary Tuberculosis2021In: Frontiers in Pharmacology, E-ISSN 1663-9812, Vol. 12, article id 637618Article in journal (Refereed)
    Abstract [en]

    Background: Meropenem is being investigated for repurposing as an anti-tuberculosis drug. This study aimed to develop a meropenem population pharmacokinetics model in patients with pulmonary tuberculosis and identify covariates explaining inter-individual variability.

    Methods: Patients were randomized to one of four treatment groups: meropenem 2 g three times daily plus oral rifampicin 20 mg/kg once daily, meropenem 2 g three times daily, meropenem 1 g three times daily, and meropenem 3 g once daily. Meropenem was administered by intravenous infusion over 0.5-1 h. All patients also received oral amoxicillin/clavulanate together with each meropenem dose, and treatments continued daily for 14 days. Intensive plasma pharmacokinetics sampling over 8 h was conducted on the 14th day of the study. Nonlinear mixed-effects modeling was used for data analysis. The best model was chosen based on likelihood metrics, goodness-of-fit plots, and parsimony. Covariates were tested stepwise.

    Results: A total of 404 concentration measurements from 49 patients were included in the analysis. A two-compartment model parameterized with clearance (CL), inter-compartmental clearance (Q), and central (V1) and peripheral (V2) volumes of distribution fitted the data well. Typical values of CL, Q, V1, and V2 were 11.8 L/h, 3.26 L/h, 14.2 L, and 3.12 L, respectively. The relative standard errors of the parameter estimates ranged from 3.8 to 35.4%. The covariate relations included in the final model were creatinine clearance on CL and allometric scaling with body weight on all disposition parameters. An effect of age on CL as previously reported could not be identified.

    Conclusion: A two-compartment model described meropenem population pharmacokinetics in patients with pulmonary tuberculosis well. Covariates found to improve model fit were creatinine clearance and body weight but not rifampicin treatment. The final model will be used for an integrated pharmacokinetics/pharmacodynamics analysis linking meropenem exposure to early bactericidal activity.

    Download full text (pdf)
    FULLTEXT01
  • 6.
    Abulfathi, Ahmed A.
    et al.
    Stellenbosch Univ, Fac Med & Hlth Sci, Dept Med, Div Clin Pharmacol, Cape Town, South Africa..
    Donald, Peter R.
    Stellenbosch Univ, Fac Med & Hlth Sci, Dept Paediat & Child Hlth, Desmond Tutu TB Ctr, Cape Town, South Africa..
    Adams, Kim
    Stellenbosch Univ, Fac Med & Hlth Sci, Dept Med, Div Clin Pharmacol, Cape Town, South Africa..
    Svensson, Elin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Radboud Univ Nijmegen, Med Ctr, Radboud Inst Hlth Sci, Dept Pharm, Nijmegen, Netherlands..
    Diacon, Andreas H.
    Task Appl Sci, Bellville, South Africa.;Stellenbosch Univ, Fac Med & Hlth Sci, Dept Med, Cape Town, South Africa..
    Reuter, Helmuth
    Stellenbosch Univ, Fac Med & Hlth Sci, Dept Med, Div Clin Pharmacol, Cape Town, South Africa..
    The pharmacokinetics of para-aminosalicylic acid and its relationship to efficacy and intolerance2020In: British Journal of Clinical Pharmacology, ISSN 0306-5251, E-ISSN 1365-2125, Vol. 86, no 11, p. 2123-2132Article, review/survey (Refereed)
    Abstract [en]

    Following its introduction as an antituberculosis agent close to 75 years ago, the use of para-aminosalicylic acid (PAS) has been limited by gastrointestinal intolerance and multiple formulations were produced in attempts to reduce its occurrence. More recently, an enteric-coated, granular, slow-release PAS formulation (PASER) was introduced and is now in wide-spread use for the treatment of drug-resistant tuberculosis. The current PASER dosing regimen is based on recommendations derived from older studies using a variety of different PAS formulations and relegate PAS to a role as an exclusively bacteriostatic agent. However, there is ample evidence that if sufficiently high serum concentrations are reached, PAS can be bactericidal and that intolerance following once daily dosing, that aids the achievement of such concentrations, is no worse than that following intermittent daily dosing. In particular, prevention of resistance to companion drugs appears to be dependent on the size of the single dose, and hence the peak concentrations, and not on maintaining serum levels consistently above minimum inhibitory concentration. We present a narrative review of the development of PAS formulations, dosing practices, and published data regarding pharmacokinetics and pharmacodynamics and the relationship of PAS dosage to intolerance and efficacy. Our conclusions suggests that we are at present not using PAS to its maximum ability to contribute to regimen efficacy and protect companion drugs.

  • 7.
    Abulfathi, Ahmed Aliyu
    et al.
    Stellenbosch Univ, Fac Med & Hlth Sci, Div Clin Pharmacol, Dept Med, POB 241, ZA-8000 Cape Town, South Africa.
    Decloedt, Eric H.
    Stellenbosch Univ, Fac Med & Hlth Sci, Div Clin Pharmacol, Dept Med, POB 241, ZA-8000 Cape Town, South Africa.
    Svensson, Elin M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Radboud Univ Nijmegen, Med Ctr, Radboud Inst Hlth Sci, Dept Pharm, Nijmegen, Netherlands.
    Diacon, Andreas H.
    Task Appl Sci, Bellville, South Africa;Stellenbosch Univ, Fac Med & Hlth Sci, Dept Med, Cape Town, South Africa.
    Donald, Peter
    Stellenbosch Univ, Fac Med & Hlth Sci, Paediat & Child Hlth & Desmond Tutu TB Ctr, Cape Town, South Africa.
    Reuter, Helmuth
    Stellenbosch Univ, Fac Med & Hlth Sci, Div Clin Pharmacol, Dept Med, POB 241, ZA-8000 Cape Town, South Africa.
    Clinical Pharmacokinetics and Pharmacodynamics of Rifampicin in Human Tuberculosis2019In: Clinical Pharmacokinetics, ISSN 0312-5963, E-ISSN 1179-1926, Vol. 58, no 9, p. 1103-1129Article, review/survey (Refereed)
    Abstract [en]

    The introduction of rifampicin (rifampin) into tuberculosis (TB) treatment five decades ago was critical for shortening the treatment duration for patients with pulmonary TB to 6months when combined with pyrazinamide in the first 2months. Resistance or hypersensitivity to rifampicin effectively condemns a patient to prolonged, less effective, more toxic, and expensive regimens. Because of cost and fears of toxicity, rifampicin was introduced at an oral daily dose of 600mg (8-12mg/kg body weight). At this dose, clinical trials in 1970s found cure rates of >= 95% and relapse rates of < 5%. However, recent papers report lower cure rates that might be the consequence of increased emergence of resistance. Several lines of evidence suggest that higher rifampicin doses, if tolerated and safe, could shorten treatment duration even further. We conducted a narrative review of rifampicin pharmacokinetics and pharmacodynamics in adults across a range of doses and highlight variables that influence its pharmacokinetics/pharmacodynamics. Rifampicin exposure has considerable inter- and intra-individual variability that could be reduced by administration during fasting. Several factors including malnutrition, HIV infection, diabetes mellitus, dose size, pharmacogenetic polymorphisms, hepatic cirrhosis, and substandard medicinal products alter rifampicin exposure and/or efficacy. Renal impairment has no influence on rifampicin pharmacokinetics when dosed at 600mg. Rifampicin maximum (peak) concentration (C-max) > 8.2 mu g/mL is an independent predictor of sterilizing activity and therapeutic drug monitoring at 2, 4, and 6h post-dose may aid in optimizing dosing to achieve the recommended rifampicin concentration of >= 8 mu g/mL. A higher rifampicin C-max is required for severe forms TB such as TB meningitis, with C-max >= 22 mu g/mL and area under the concentration-time curve (AUC) from time zero to 6h (AUC(6)) >= 70 mu g.h/mL associated with reduced mortality. More studies are needed to confirm whether doses achieving exposures higher than the current standard dosage could translate into faster sputum conversion, higher cure rates, lower relapse rates, and less mortality. It is encouraging that daily rifampicin doses up to 35mg/kg were found to be safe and well-tolerated over a period of 12weeks. High-dose rifampicin should thus be considered in future studies when constructing potentially shorter regimens. The studies should be adequately powered to determine treatment outcomes and should include surrogate markers of efficacy such as C-max/MIC (minimum inhibitory concentration) and AUC/MIC.

  • 8.
    Alffenaar, J. W. C.
    et al.
    Univ Sydney, Sydney Inst Infect Dis, Sydney, NSW, Australia.;Univ Sydney, Sch Pharm, Fac Med & Hlth, Sydney, NSW, Australia.;Westmead Hosp, Sydney, NSW, Australia.
    Stocker, S. L.
    Univ Sydney, Sch Pharm, Fac Med & Hlth, Sydney, NSW, Australia.;St Vincents Hosp, Dept Clin Pharmacol & Toxicol, Sydney, NSW, Australia.;Univ NSW, St Vincents Clin Campus, Kensington, NSW, Australia.
    Forsman, L. Davies
    Karolinska Inst, Dept Med, Div Infect Dis, Solna, Sweden.;Karolinska Univ Hosp, Dept Infect Dis, Solna, Sweden.
    Garcia-Prats, A.
    Stellenbosch Univ, Desmond Tutu TB Ctr, Dept Paediat & Child Hlth, Tygerberg, South Africa.;Univ Wisconsin, Dept Pediat, Madison, WI USA.
    Heysell, S. K.
    Univ Virginia, Div Infect Dis & Int Hlth, Charlottesville, VA USA.
    Aarnoutse, R. E.
    Radboud Univ Nijmegen Med Ctr, Radboud Inst Hlth Sci, Dept Pharm, Nijmegen, Netherlands.;Radboud Univ Nijmegen Med Ctr, Radboudumc Ctr Infect Dis, Nijmegen, Netherlands.
    Akkerman, O. W.
    Univ Groningen, Univ Med Ctr Groningen, Dept Pulm Dis & TB, Groningen, Netherlands.;Univ Groningen, Univ Med Ctr Groningen, TB Ctr Beatrixoord, Haren, Netherlands.
    Aleksa, A.
    Grodno State Med Univ, Educ Inst, Grodno, BELARUS.
    van Altena, R.
    Asian Harm Reduct Network AHRN, Yangon, Myanmar.;Med Act Myanmar MAM, Yangon, Myanmar.
    de Onata, W. Arrazola
    Belgian Sci Inst Publ Hlth, Belgian Lung & TB Assoc, Brussels, Belgium.
    Bhavani, P. K.
    Indian Council Med Res Natl Inst Res TB, Int Ctr Excellence Res, Chennai, Tamil Nadu, India.
    Van't Boveneind-Vrubleuskaya, N.
    Univ Groningen, Univ Med Ctr Groningen, Dept Clin Pharm & Pharmacol, Groningen, Netherlands.;Metropolitan Publ Hlth Serv, Dept Publ Hlth TB Control, The Hague, Netherlands.
    Carvalho, A. C. C.
    Fundacao Oswaldo Cruz, Lab Inovacoes Terapias Ensino & Bioprod LITEB, Inst Oswaldo Cruz, Rio De Janeiro, RJ, Brazil.
    Centis, R.
    Ist Ricovero & Cura Carattere Sci IRCCS, Ist Clin Sci Maugeri, Serv Epidemiol Clin Malattie Resp, Tradate, Italy.
    Chakaya, J. M.
    Kenyatta Univ, Dept Med Therapeut & Dermatol, Nairobi, Kenya.;Univ Liverpool Liverpool Sch Trop Med, Dept Clin Sci, Liverpool, Merseyside, England.
    Cirillo, D. M.
    IRCCS San Raffaele Sci Inst, Div Immunol Transplantat & Infect Dis, Emerging Bacterial Pathogens Unit, Milan, Italy.
    Cho, J. G.
    Univ Sydney, Sydney Inst Infect Dis, Sydney, NSW, Australia.;Westmead Hosp, Sydney, NSW, Australia.;Parramatta Chest Clin, Parramatta, NSW, Australia.
    Ambrosio, L. D.
    Publ Hlth Consulting Grp, Lugano, Switzerland.
    Dalcolmo, M. P.
    Funda Oswaldo Cruz Fiocruz, Reference Ctr Helio Fraga, Rio De Janeiro, RJ, Brazil.
    Denti, P.
    Univ Cape Town, Dept Med, Div Clin Pharmacol, Cape Town, South Africa.
    Dheda, K.
    Univ Cape Town, Ctr Lung Infect & Immun, Div Pulmonol, Dept Med, Cape Town, South Africa.;Univ Cape Town, UCT Lung Inst, Cape Town, South Africa.;Univ Cape Town Lung Inst, Cape Town, South Africa.;South African MRC Ctr Study Antimicrobial Resista, Cape Town, South Africa.;London Sch Hyg & Trop Med, Fac Infect & Trop Dis, Dept Immunol & Infect, London, England.
    Fox, G. J.
    Univ Sydney, Fac Med & Hlth, Sydney Med Sch, Sydney, NSW, Australia.;Woolcock Inst Med Res, Glebe, NSW, Australia.
    Hesseling, A. C.
    Stellenbosch Univ, Desmond Tutu TB Ctr, Dept Paediat & Child Hlth, Tygerberg, South Africa.
    Kim, H. Y.
    Univ Sydney, Sydney Inst Infect Dis, Sydney, NSW, Australia.;Univ Sydney, Sch Pharm, Fac Med & Hlth, Sydney, NSW, Australia.;Westmead Hosp, Sydney, NSW, Australia.
    Koser, C. U.
    Univ Cambridge, Dept Genet, Cambridge, England.
    Marais, B. J.
    Univ Sydney, Sydney Inst Infect Dis, Sydney, NSW, Australia.;Childrens Hosp Westmead, Dept Infect Dis & Microbiol, Westmead, NSW, Australia.
    Margineanu, I
    Univ Groningen, Univ Med Ctr Groningen, Dept Clin Pharm & Pharmacol, Groningen, Netherlands.
    Martson, A. G.
    Univ Liverpool, Inst Translat Med, Dept Mol & Clin Pharmacol, Liverpool, Merseyside, England.
    Torrico, M. Munoz
    Inst Nacl Enfermedades Resp, Clin TB, Ciudad De Mexico, Mexico.
    Nataprawira, H. M.
    Univ Padjadjaran, Hasan Sadikin Hosp, Fac Med, Dept Child Hlth,Div Paediat Respirol, Bandung, Indonesia.
    Ong, C. W. M.
    Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Med, Infect Dis Translat Res Programme, Singapore, Singapore.;Natl Univ Singapore, Inst Hlth Innovat & Technol iHealthtech, Singapore, Singapore.;Natl Univ Singapore Hosp, Dept Med, Div Infect Dis, Singapore, Singapore.
    Otto-Knapp, R.
    German Cent Comm TB DZK, Berlin, Germany.
    Peloquin, C. A.
    Univ Florida, Infect Dis Pharmacokinet Lab, Pharmacitherapy & Translat Res, Coll Pharm, Gainesville, FL USA.
    Silva, D. R.
    Univ Fed Rio Grande do Sul, Fac Med, Porto Alegre, RS, Brazil.
    Ruslami, R.
    Univ Padjadjaran, Fac Med, TB HIV Res Ctr, Bandung, Indonesia.;Univ Padjadjaran, Fac Med, Dept Biomed Sci, Div Pharmacol & Therapy, Bandung, Indonesia.
    Santoso, P.
    Univ Padjadjaran, Fac Med, Dept Internal Med, Div Respirol & Crit Care,Hasan Sadikin Gen Hosp, Bandung, Indonesia.
    Savic, R. M.
    Univ Calif San Francisco, Sch Pharm, Dept Bioengn & Therapeut Sci, Div Pulm & Crit Care Med, San Francisco, CA USA.;Univ Calif San Francisco, Sch Med, Div Pulm & Crit Care Med, Dept Bioengn & Therapeut Sci, San Francisco, CA USA.
    Singla, R.
    Natl Inst TB & Resp Dis, Dept TB & Resp Dis, New Delhi, India.
    Svensson, Elin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Radboud Univ Nijmegen Med Ctr, Radboud Inst Hlth Sci, Dept Pharm, Nijmegen, Netherlands.;Radboud Univ Nijmegen Med Ctr, Radboudumc Ctr Infect Dis, Nijmegen, Netherlands.
    Skrahina, A.
    Republican Res & Pract Ctr Pulmonol & TB, Minsk, BELARUS.
    van Soolingen, D.
    Natl Inst Publ Hlth & Environm, TB Reference Lab RIVM, Bilthoven, Netherlands.
    Srivastava, S.
    Univ Texas Hlth Sci Ctr Tyler, Dept Pulm Immunol, Tyler, TX USA.
    Tadolini, M.
    IRCCS Azienda Osped Univ Bologna, Infect Dis Unit, Bologna, Italy.;Alma Mater Studiorum Univ Bologna, Dept Med & Surg Sci, Bologna, Italy.
    Tiberi, S.
    Queen Mary Univ London, Barts & London Sch Med & Dent, Blizard Inst, London, England.
    Thomas, T. A.
    Univ Virginia, Div Infect Dis & Int Hlth, Charlottesville, VA USA.
    Udwadia, Z. F.
    PD Hinduja Natl Hosp & Med Res Ctr, Mumbai, Maharashtra, India.
    Vu, D. H.
    Hanoi Univ Pharm, Natl Drug Informat & Adverse Drug React Monitorin, Hanoi, Vietnam.
    Zhang, W.
    Fudan Univ, Huashan Hosp, Shanghai Med Coll,Shanghai Key Lab Infect Dis & B, Natl Med Ctr Infect Dis,Dept Infect Dis, Shanghai, Peoples R China.
    Mpagama, S. G.
    Kilimanjaro Christian Med Univ Coll, Moshi, Tanzania.;Kibongoto Infect Dis Hosp, Siha, Kilimanjaro, Tanzania.
    Schon, T.
    Linköping Univ Hosp, Dept Infect Dis, Linköping, Sweden.;Linköping Univ, Inst Biomed & Clin Sci, Div Infect & Inflammat, Linköping, Sweden.;Linköping Univ, Kalmar Cty Hosp, Dept Infect Dis, Linköping, Sweden.
    Migliori, G. B.
    Grodno State Med Univ, Educ Inst, Grodno, BELARUS.
    Clinical standards for the dosing and management of TB drugs2022In: The International Journal of Tuberculosis and Lung Disease, ISSN 1027-3719, E-ISSN 1815-7920, Vol. 26, no 6, p. 483-+Article in journal (Other academic)
    Abstract [en]

    Background: Optimal drug dosing is important to ensure adequate response to treatment, prevent development of drug resistance and reduce drug toxicity. The aim of these clinical standards is to provide guidance on 'best practice' for dosing and management of TB drugs.

    Methods: A panel of 57 global experts in the fields of microbiology, pharmacology and TB care were identified; 51 participated in a Delphi process. A 5-point Likert scale was used to score draft standards. The final document represents the broad consensus and was approved by all participants.

    Results: Six clinical standards were defined: Standard 1, defining the most appropriate initial dose for TB treatment; Standard 2, identifying patients who may be at risk of sub-optimal drug exposure; Standard 3, identifying patients at risk of developing drug-related toxicity and how best to manage this risk; Standard 4, identifying patients who can benefit from therapeutic drug monitoring (TDM); Standard 5, highlighting education and counselling that should be provided to people initiating TB treatment; and Standard 6, providing essential education for healthcare professionals. In addition, consensus research priorities were identified.

    Conclusion: This is the first consensus-based Clinical Standards for the dosing and management of TB drugs to guide clinicians and programme managers in planning and implementation of locally appropriate measures for optimal person-centred treatment to improve patient care.

  • 9.
    Ayoun Alsoud, Rami
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Svensson, Robin J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Svensson, Elin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Radboud Univ Nijmegen, Radboud Inst Hlth Sci, Dept Pharm, Med Ctr, Nijmegen, Netherlands..
    Gillespie, Stephen H. H.
    Univ St Andrews, Sch Med, Div Infect & Global Hlth, St Andrews, Scotland..
    Boeree, Martin J. J.
    Radboud Univ Nijmegen, Dept Lung Dis, Med Ctr, Nijmegen, Netherlands..
    Diacon, Andreas H. H.
    TASK Appl Sci, Cape Town, South Africa..
    Dawson, Rodney
    Univ Cape Town, Dept Med, Div Pulmonol, Cape Town, South Africa.;Univ Cape Town, Lung Inst, Cape Town, South Africa..
    Aarnoutse, Rob E. E.
    Radboud Univ Nijmegen, Radboud Inst Hlth Sci, Dept Pharm, Med Ctr, Nijmegen, Netherlands..
    Simonsson, Ulrika S. H.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Combined quantitative tuberculosis biomarker model for time-to-positivity and colony forming unit to support tuberculosis drug development2023In: Frontiers in Pharmacology, E-ISSN 1663-9812, Vol. 14, article id 1067295Article in journal (Refereed)
    Abstract [en]

    Biomarkers are quantifiable characteristics of biological processes. In Mycobacterium tuberculosis, common biomarkers used in clinical drug development are colony forming unit (CFU) and time-to-positivity (TTP) from sputum samples. This analysis aimed to develop a combined quantitative tuberculosis biomarker model for CFU and TTP biomarkers for assessing drug efficacy in early bactericidal activity studies. Daily CFU and TTP observations in 83 previously patients with uncomplicated pulmonary tuberculosis after 7 days of different rifampicin monotherapy treatments (10-40 mg/kg) from the HIGHRIF1 study were included in this analysis. The combined quantitative tuberculosis biomarker model employed the Multistate Tuberculosis Pharmacometric model linked to a rifampicin pharmacokinetic model in order to determine drug exposure-response relationships on three bacterial sub-states using both the CFU and TTP data simultaneously. CFU was predicted from the MTP model and TTP was predicted through a time-to-event approach from the TTP model, which was linked to the MTP model through the transfer of all bacterial sub-states in the MTP model to a one bacterial TTP model. The non-linear CFU-TTP relationship over time was well predicted by the final model. The combined quantitative tuberculosis biomarker model provides an efficient approach for assessing drug efficacy informed by both CFU and TTP data in early bactericidal activity studies and to describe the relationship between CFU and TTP over time.

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  • 10.
    Brill, Margreke JE
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Svensson, Elin M
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Pandie, Mishal
    Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa.
    Maartens, Gary
    Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa.
    Karlsson, Mats O
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Confirming model-predicted pharmacokinetic interactions between bedaquiline and lopinavir/ritonavir or nevirapine in patients with HIV and drug resistant tuberculosis2017In: International Journal of Antimicrobial Agents, ISSN 0924-8579, E-ISSN 1872-7913, Vol. 49, p. 212-217Article in journal (Refereed)
    Abstract [en]

    Bedaquiline and its metabolite M2 are metabolised by CYP3A4. The antiretrovirals ritonavir-boosted lopinavir (LPV/r) and nevirapine inhibit and induce CYP3A4, respectively. Here we aimed to quantify nevirapine and LPV/r drug–drug interaction effects on bedaquiline and M2 in patients co-infected with HIV and multidrug-resistant tuberculosis (MDR-TB) using population pharmacokinetic (PK) analysis and compare these with model-based predictions from single-dose studies in subjects without TB. An observational PK study was performed in three groups of MDR-TB patients during bedaquiline maintenance dosing: HIV-seronegative patients (n = 17); and HIV-infected patients using antiretroviral therapy including nevirapine (n = 17) or LPV/r (n = 14). Bedaquiline and M2 samples were collected over 48 h post-dose. A previously developed PK model of MDR-TB patients was used as prior information to inform parameter estimation using NONMEM. The model was able to describe bedaquiline and M2 concentrations well, with estimates close to their priors and earlier model-based interaction effects from single-dose studies. Nevirapine changed bedaquiline clearance to 82% (95% CI 67–99%) and M2 clearance to 119% (92–156%) of their original values, indicating no clinically significant interaction. LPV/r substantially reduced bedaquiline clearance to 25% (17–35%) and M2 clearance to 59% (44–69%) of original values. This work confirms earlier model-based predictions of nevirapine and LPV/r interaction effects on bedaquiline and M2 clearance from subjects without TB in single-dose studies, in MDR-TB/HIV co-infected patients studied here. To normalise bedaquiline exposure in patients with concomitant LPV/r therapy, an adjusted bedaquiline dosing regimen is proposed for further study.

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  • 11.
    Bukkems, V. E.
    et al.
    Radboud Univ Nijmegen, Radboud Inst Hlth Sci RIHS, Dept Pharm, Med Ctr, Nijmegen, Netherlands.
    van Hove, H.
    Radboud Univ Nijmegen, Dept Pharmacol & Toxicol, Med Ctr, Nijmegen, Netherlands.
    Roelofsen, D.
    Radboud Univ Nijmegen, Radboud Inst Hlth Sci RIHS, Dept Pharm, Med Ctr, Nijmegen, Netherlands.;Radboud Univ Nijmegen, Dept Pharmacol & Toxicol, Med Ctr, Nijmegen, Netherlands.
    Freriksen, J. J. M.
    Radboud Univ Nijmegen, Dept Pharmacol & Toxicol, Med Ctr, Nijmegen, Netherlands.
    Kolmer, E. W. J. Van Ewijk-Beneken
    Radboud Univ Nijmegen, Radboud Inst Hlth Sci RIHS, Dept Pharm, Med Ctr, Nijmegen, Netherlands.
    Burger, D. M.
    Radboud Univ Nijmegen, Radboud Inst Hlth Sci RIHS, Dept Pharm, Med Ctr, Nijmegen, Netherlands.
    van Drongelen, J.
    Radboud Univ Nijmegen, Dept Obstet & Gynaecol, Med Ctr, Nijmegen, Netherlands.
    Svensson, Elin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Radboud Univ Nijmegen, Radboud Inst Hlth Sci RIHS, Dept Pharm, Med Ctr, Nijmegen, Netherlands.
    Greupink, R.
    Radboud Univ Nijmegen, Dept Pharmacol & Toxicol, Med Ctr, Nijmegen, Netherlands.
    Colbers, A.
    Radboud Univ Nijmegen, Radboud Inst Hlth Sci RIHS, Dept Pharm, Med Ctr, Nijmegen, Netherlands.
    Prediction of Maternal and Fetal Doravirine Exposure by Integrating Physiologically Based Pharmacokinetic Modeling and Human Placenta Perfusion Experiments2022In: Clinical Pharmacokinetics, ISSN 0312-5963, E-ISSN 1179-1926, Vol. 61, no 8, p. 1129-1141Article in journal (Refereed)
    Abstract [en]

    Background and Objective Doravirine is currently not recommended for pregnant women living with human immunodeficiency virus because efficacy and safety data are lacking. This study aimed to predict maternal and fetal doravirine exposure by integrating human placenta perfusion experiments with pregnancy physiologically based pharmacokinetic (PBPK) modeling.

    Methods Ex vivo placenta perfusions were performed in a closed-closed configuration, in both maternal-to-fetal and fetal-to-maternal directions (n = 8). To derive intrinsic placental transfer parameters from perfusion data, we developed a mechanistic placenta model. Next, we developed a maternal and fetal full-body pregnancy PBPK model for doravirine in Simcyp, which was parameterized with the derived intrinsic placental transfer parameters to predict in vivo maternal and fetal doravirine exposure at 26, 32, and 40 weeks of pregnancy. The predicted total geometric mean (GM) trough plasma concentration (C-trough) values were compared with the target (0.23 mg/L) derived from in vivo exposure-response analysis.

    Results A decrease of 55% in maternal doravirine area under the plasma concentration-time curve (AUC)(0-24h) was predicted in pregnant women at 40 weeks of pregnancy compared with nonpregnant women. At 26, 32, and 40 weeks of pregnancy, predicted maternal total doravirine GM C-trough values were below the predefined efficacy target of 0.23 mg/L. Perfusion experiments showed that doravirine extensively crossed the placenta, and PBPK modeling predicted considerable fetal doravirine exposure.

    Conclusion Substantially reduced maternal doravirine exposure was predicted during pregnancy, possibly resulting in impaired efficacy. Therapeutic drug and viral load monitoring are advised for pregnant women treated with doravirine. Considerable fetal doravirine exposure was predicted, highlighting the need for clinical fetal safety data.

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  • 12.
    Bukkems, Vera E.
    et al.
    Radboud Univ Nijmegen, Med Ctr, Radboud Inst Hlth Sci RIHS, Dept Pharm, Nijmegen, Netherlands..
    Post, Teun M.
    Leiden Experts Adv Pharmacokinet & Pharmacodynam, Leiden, Netherlands..
    Colbers, Angela P.
    Radboud Univ Nijmegen, Med Ctr, Radboud Inst Hlth Sci RIHS, Dept Pharm, Nijmegen, Netherlands..
    Burger, David M.
    Radboud Univ Nijmegen, Med Ctr, Radboud Inst Hlth Sci RIHS, Dept Pharm, Nijmegen, Netherlands..
    Svensson, Elin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Radboud Univ Nijmegen, Med Ctr, Radboud Inst Hlth Sci RIHS, Dept Pharm, Nijmegen, Netherlands..
    A population pharmacokinetics analysis assessing the exposure of raltegravir once-daily 1200 mg in pregnant women living with HIV2021In: CPT: Pharmacometrics and Systems Pharmacology (PSP), E-ISSN 2163-8306, Vol. 10, no 2, p. 161-172Article in journal (Refereed)
    Abstract [en]

    Once-daily two 600 mg tablets (1200 mg q.d.) raltegravir offers an easier treatment option compared to the twice-daily regimen of one 400 mg tablet. No pharmacokinetic, efficacy, or safety data of the 1200 mg q.d. regimen have been reported in pregnant women to date as it is challenging to collect these clinical data. This study aimed to develop a population pharmacokinetic (PopPK) model to predict the pharmacokinetic profile of raltegravir 1200 mg q.d. in pregnant women and to discuss the expected pharmacodynamic properties of raltegravir 1200 mg q.d. during pregnancy based on previously reported concentration-effect relationships. Data from 11 pharmacokinetic studies were pooled (n = 221). A two-compartment model with first-order elimination and absorption through three sequential transit compartments best described the data. We assessed that the bio-availability of the 600 mg tablets was 21% higher as the 400 mg tablets, and the bio-availability in pregnant women was 49% lower. Monte-Carlo simulations were performed to predict the pharmacokinetic profile of 1200 mg q.d. in pregnant and nonpregnant women. The primary criteria for efficacy were that the lower bound of the 90% confidence interval (CI) of the concentration before next dose administration (C-trough) geometric mean ratio (GMR) of simulated pregnant/nonpregnant women had to be greater than 0.75. The simulated raltegravir C-trough GMR (90% CI) was 0.51 (0.41-0.63), hence not meeting the primary target for efficacy. Clinical data from two pregnant women using 1200 mg q.d. raltegravir showed a similar C-trough ratio pregnant/nonpregnant. Our pharmacokinetic results support the current recommendation of not using the raltegravir 1200 mg q.d. regimen during pregnancy until more data on the exposure-response relationship becomes available.

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  • 13.
    Cresswell, Fiona, V
    et al.
    London Sch Hyg & Trop Med, Clin Res Dept, Keppel St, London WC1E 7HT, England.;Makerere Univ, Infect Dis Inst, Kampala, Uganda.;Uganda Virus Res Inst, Med Res Council, LSHIM Uganda Res Unit, Entebbe, Uganda..
    Meya, David B.
    Makerere Univ, Infect Dis Inst, Kampala, Uganda..
    Kagimu, Enock
    Makerere Univ, Infect Dis Inst, Kampala, Uganda..
    Grint, Daniel
    London Sch Hyg & Trop Med, Trop Epidemiol Grp, Keppel St, London, England..
    Te Brake, Lindsey
    Radboud Univ Nijmegen Med Ctr, Radboud Inst Hlth Sci, Dept Pharm, Nijmegen, Netherlands..
    Kasibante, John
    Makerere Univ, Infect Dis Inst, Kampala, Uganda..
    Martyn, Emily
    London Sch Hyg & Trop Med, Clin Res Dept, Keppel St, London WC1E 7HT, England..
    Rutakingirwa, Morris
    Makerere Univ, Infect Dis Inst, Kampala, Uganda..
    Quinn, Carson M.
    Univ Calif San Francisco, San Francisco, CA 94143 USA..
    Okirwoth, Micheal
    Makerere Univ, Infect Dis Inst, Kampala, Uganda..
    Tugume, Lillian
    Makerere Univ, Infect Dis Inst, Kampala, Uganda..
    Ssembambulidde, Kenneth
    Makerere Univ, Infect Dis Inst, Kampala, Uganda..
    Musubire, Abdu K.
    Makerere Univ, Infect Dis Inst, Kampala, Uganda..
    Bangdiwala, Ananta S.
    Univ Minnesota, Div Biostat, Minneapolis, MN USA..
    Buzibye, Allan
    Makerere Univ, Infect Dis Inst, Kampala, Uganda..
    Muzoora, Conrad
    Mbarara Univ Sci & Technol, Mbarara, Uganda..
    Svensson, Elin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Radboud Univ Nijmegen Med Ctr, Radboud Inst Hlth Sci, Dept Pharm, Nijmegen, Netherlands..
    Aarnoutse, Rob
    Radboud Univ Nijmegen Med Ctr, Radboud Inst Hlth Sci, Dept Pharm, Nijmegen, Netherlands..
    Boulware, David R.
    Univ Minnesota, Div Infect Dis & Int Med, Minneapolis, MN USA..
    Elliott, Alison M.
    London Sch Hyg & Trop Med, Clin Res Dept, Keppel St, London WC1E 7HT, England.;Uganda Virus Res Inst, Med Res Council, LSHIM Uganda Res Unit, Entebbe, Uganda..
    High-Dose Oral and Intravenous Rifampicin for the Treatment of Tuberculous Meningitis in Predominantly Human Immunodeficiency Virus (HIV)-Positive Ugandan Adults: A Phase II Open-Label Randomized Controlled Trial2021In: Clinical Infectious Diseases, ISSN 1058-4838, E-ISSN 1537-6591, Vol. 73, no 5, p. 876-884Article in journal (Refereed)
    Abstract [en]

    Background: High-dose rifampicin may improve outcomes of tuberculous meningitis (TBM). Little safety or pharmacokinetic (PK) data exist on high-dose rifampicin in human immunodeficiency virus (HIV) coinfection, and no cerebrospinal fluid (CSF) PK data exist from Africa. We hypothesized that high-dose rifampicin would increase serum and CSF concentrations without excess toxicity. Methods: In this phase II open-label trial, Ugandan adults with suspected TBM were randomized to standard-of-care control (PO-10, rifampicin 10 mg/kg/day), intravenous rifampicin (IV-20, 20 mg/kg/day), or high-dose oral rifampicin (PO-35, 35 mg/kg/day). We performed PK sampling on days 2 and 14. The primary outcomes were total exposure (AUC(0-24)), maximum concentration (C-max), CSF concentration, and grade 3-5 adverse events. Results: We enrolled 61 adults, 92% were living with HIV, median CD4 count was 50 cells/mu L (interquartile range [IQR] 46-56). On day 2, geometric mean plasma AUC(0-24hr) was 42.9.h mg/L with standard-of-care 10 mg/kg dosing, 249.h mg/L for IV-20 and 327.h mg/L for PO-35 (P<.001). In CSF, standard of care achieved undetectable rifampicin concentration in 56% of participants and geometric mean AUC(0-24hr) 0.27 mg/L, compared with 1.74 mg/L (95% confidence interval [CI] 1.2-2.5) for IV-20 and 2.17 mg/L (1.6-2.9) for PO-35 regimens (P<.001). Achieving CSF concentrations above rifampicin minimal inhibitory concentration (MIC) occurred in 11% (2/18) of standard-of-care, 93% (14/15) of IV-20, and 95% (18/19) of PO-35 participants. Higher serum and CSF levels were sustained at day 14. Adverse events did not differ by dose (P=.34). Conclusions: Current international guidelines result in sub-therapeutic CSF rifampicin concentration for 89% of Ugandan TBM patients. High-dose intravenous and oral rifampicin were safe and respectively resulted in exposures similar to 6- and similar to 8-fold higher than standard of care, and CSF levels above the MIC.

  • 14.
    Danho, Rabi
    et al.
    Radboud Univ Nijmegen Med Ctr, Radboud Univ Med Ctr Infect Dis, Dept Med Microbiol, Nijmegen, Netherlands..
    Schildkraut, Jodie A.
    Radboud Univ Nijmegen Med Ctr, Radboud Univ Med Ctr Infect Dis, Dept Med Microbiol, Nijmegen, Netherlands..
    Zweijpfenning, Sanne M. H.
    Radboud Univ Nijmegen Med Ctr, Radboud Univ Med Ctr Infect Dis, Dept Pulm Dis, Nijmegen, Netherlands..
    Svensson, Elin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Radboud Univ Nijmegen Med Ctr, Radboud Univ Med Ctr Infect Dis, Dept Pharm, Nijmegen, Netherlands.
    Pennings, Lian J.
    Radboud Univ Nijmegen Med Ctr, Radboud Univ Med Ctr Infect Dis, Dept Med Microbiol, Nijmegen, Netherlands..
    Kuipers, Saskia
    Radboud Univ Nijmegen Med Ctr, Radboud Univ Med Ctr Infect Dis, Dept Med Microbiol, Nijmegen, Netherlands..
    Wertheim, Heiman F. L.
    Radboud Univ Nijmegen Med Ctr, Radboud Univ Med Ctr Infect Dis, Dept Med Microbiol, Nijmegen, Netherlands..
    Boeree, Martin J.
    Radboud Univ Nijmegen Med Ctr, Radboud Univ Med Ctr Infect Dis, Dept Pulm Dis, Nijmegen, Netherlands..
    Hoefsloot, Wouter
    Radboud Univ Nijmegen Med Ctr, Radboud Univ Med Ctr Infect Dis, Dept Pulm Dis, Nijmegen, Netherlands..
    van Ingen, Jakko
    Radboud Univ Nijmegen Med Ctr, Radboud Univ Med Ctr Infect Dis, Dept Med Microbiol, Nijmegen, Netherlands..
    Mycobacterium Growth Indicator Tube Time-To-Positivity Can Serve As an Early Biomarker of Treatment Response in Mycobacterium avium Complex Pulmonary Disease2022In: Chest, ISSN 0012-3692, E-ISSN 1931-3543, Vol. 161, no 2, p. 370-372Article in journal (Other academic)
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  • 15.
    De Jager, Veronique
    et al.
    TASK Appl Sci, Cape Town, South Africa..
    Gupte, Nikhil
    Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21287 USA.;Johns Hopkins India, Pune, Maharashtra, India..
    Nunes, Silvia
    TASK Appl Sci, Cape Town, South Africa..
    Barnes, Grace L.
    Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21287 USA..
    Van Wijk, Rob C
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Mostert, Joni
    TASK Appl Sci, Cape Town, South Africa..
    Dorman, Susan E.
    Med Univ South Carolina, Charleston, SC 29425 USA..
    Abulfathi, Ahmed A.
    Stellenbosch Univ, Dept Med, Cape Town, South Africa.;Univ Maiduguri, Dept Clin Pharmacol & Therapeut, Maiduguri, Nigeria..
    Upton, Caryn M.
    TASK Appl Sci, Cape Town, South Africa..
    Faraj, Alan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Nuermberger, Eric L.
    Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21287 USA..
    Lamichhane, Gyanu
    Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21287 USA..
    Svensson, Elin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Radboud Univ Nijmegen, Dept Pharm, Njimegen, Netherlands..
    Simonsson, Ulrika S. H.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Diacon, Andreas H.
    TASK Appl Sci, Cape Town, South Africa..
    Dooley, Kelly E.
    Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21287 USA..
    Early Bactericidal Activity of Meropenem plus Clavulanate (with or without Rifampin) for Tuberculosis: The COMRADE Randomized, Phase 2A Clinical Trial2022In: American Journal of Respiratory and Critical Care Medicine, ISSN 1073-449X, E-ISSN 1535-4970, Vol. 205, no 10, p. 1228-1235Article in journal (Refereed)
    Abstract [en]

    Rationale: Carbapenems are recommended for treatment of drug-resistant tuberculosis. Optimal dosing remains uncertain.

    Objectives: To evaluate the 14-day bactericidal activity of meropenem, at different doses, with or without rifampin.

    Methods: Individuals with drug-sensitive pulmonary tuberculosis were randomized to one of four intravenous meropenem-based arms: 2 g every 8 hours (TID) (arm C), 2 g TID plus rifampin at 20 mg/kg once daily (arm D), 1 g TID (arm E), or 3 g once daily (arm F). All participants received amoxicillin/clavulanate with each meropenem dose. Serial overnight sputum samples were collected from baseline and throughout treatment. Median daily fall in colony-forming unit (CFU) counts per milliliter of sputum (solid culture) (EBA(CFU0-14)) and increase in time to positive culture (TTP) in liquid media were estimated with mixed-effects modeling. Serial blood samples were collected for pharmacokinetic analysis on Day 13.

    Measurements and Main Results: Sixty participants enrolled. Median EBA(CFU0-14) counts (2.5th-97.5th percentiles) were 0.22 (0.12-0.33), 0.12 (0.057-0.21), 0.059 (0.033-0.097), and 0.053 (0.035-0.081); TTP increased by 0.34 (0.21-0.75), 0.11 (0.052-037), 0.094 (0.034-0.23), and 0.12 (0.04-0.41) (log(10) h), for arms C-F, respectively. Meropenem pharmacokinetics were not affected by rifampin coadministration. Twelve participants withdrew early, many of whom cited gastrointestinal adverse events.

    Conclusions: Bactericidal activity was greater with the World Health Organization-recommended total daily dose of 6 g daily than with a lower dose of 3 g daily. This difference was only detectable with solid culture. Tolerability of intravenous meropenem, with amoxicillin/clavulanate, though, was poor at all doses, calling into question the utility of this drug in second-line regimens.

  • 16.
    de Rouw, Nikki
    et al.
    Radboud Univ Nijmegen, Med Ctr, Radboud Inst Hlth Sci, Dept Pharm, POB 9101, NL-6500 HB Nijmegen, Netherlands.;Jeroen Bosch Hosp, Dept Pharm, Shertogenbosch, Netherlands..
    Boosman, Rene J.
    Netherlands Canc Inst, Dept Pharm & Pharmacol, Amsterdam, Netherlands..
    Huitema, Alwin D. R.
    Netherlands Canc Inst, Dept Pharm & Pharmacol, Amsterdam, Netherlands.;Univ Utrecht, Med Ctr, Dept Clin Pharm, Utrecht, Netherlands..
    Hilbrands, Luuk B.
    Radboud Univ Nijmegen, Med Ctr, Dept Nephrol, Nijmegen, Netherlands..
    Svensson, Elin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Radboud Univ Nijmegen, Med Ctr, Radboud Inst Hlth Sci, Dept Pharm, POB 9101, NL-6500 HB Nijmegen, Netherlands..
    Derijks, Hieronymus J.
    Radboud Univ Nijmegen, Med Ctr, Radboud Inst Hlth Sci, Dept Pharm, POB 9101, NL-6500 HB Nijmegen, Netherlands.;Jeroen Bosch Hosp, Dept Pharm, Shertogenbosch, Netherlands..
    van den Heuvel, Michel M.
    Radboud Univ Nijmegen, Med Ctr, Dept Pulm Dis, Nijmegen, Netherlands..
    Burger, David M.
    Radboud Univ Nijmegen, Med Ctr, Radboud Inst Hlth Sci, Dept Pharm, POB 9101, NL-6500 HB Nijmegen, Netherlands..
    ter Heine, Rob
    Radboud Univ Nijmegen, Med Ctr, Radboud Inst Hlth Sci, Dept Pharm, POB 9101, NL-6500 HB Nijmegen, Netherlands..
    Rethinking the Application of Pemetrexed for Patients with Renal Impairment: A Pharmacokinetic Analysis2021In: Clinical Pharmacokinetics, ISSN 0312-5963, E-ISSN 1179-1926, Vol. 60, no 5, p. 649-654Article in journal (Refereed)
    Abstract [en]

    Background Pemetrexed is used for the treatment for non-small cell lung cancer and mesothelioma. Patients with renal impairment are withheld treatment with this drug as it is unknown what dose is well tolerated in this population. Objective The purpose of our study was to investigate the pharmacokinetics (PK) of pemetrexed in patients with renal impairment. Methods A population PK analysis of pemetrexed was performed using non-linear mixed-effects modelling with phase I data obtained from the manufacturer. Additionally, the impact of renal function on pemetrexed PK was assessed with a simulation study using the developed PK model and a previously developed PK model lacking the phase I data. Results The dataset included 548 paired observations of 47 patients, with a wide range of estimated glomerular filtration rates (eGFR; 14.4-145.6 mL/min). Pemetrexed PK were best described by a three-compartment model with eGFR (calculated using the Chronic Kidney Disease-Epidemiology Collaboration [CKD-EPI] formula) as a linear covariate on renal pemetrexed clearance. Using the developed model, we found that renal clearance accounts for up to 84% (95% confidence interval 69-98%) of total pemetrexed clearance, whereas the manufacturer previously reported a 50% contribution of renal clearance. Conclusion Renal function is more important for the clearance of pemetrexed than previously thought and this should be taken into account in patients with renal impairment. Furthermore, a third compartment may contribute to prolonged exposure to pemetrexed during drug washout.

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  • 17.
    Denti, Paolo
    et al.
    Univ Cape Town, Div Clin Pharmacol, Dept Med, Cape Town, South Africa..
    Wasmann, Roeland E.
    Univ Cape Town, Div Clin Pharmacol, Dept Med, Cape Town, South Africa..
    van Rie, Annelies
    Univ Antwerp, Family Med & Populat Hlth, Fac Med, Antwerp, Belgium..
    Winckler, Jana
    Stellenbosch Univ, Dept Paediat & Child Hlth, Desmond Tutu TB Ctr, Fac Med & Hlth Sci, Cape Town, South Africa..
    Bekker, Adrie
    Stellenbosch Univ, Dept Paediat & Child Hlth, Desmond Tutu TB Ctr, Fac Med & Hlth Sci, Cape Town, South Africa..
    Rabie, Helena
    Stellenbosch Univ, Dept Paediat & Child Hlth, Cape Town, South Africa.;Stellenbosch Univ, FAMily Ctr Res Ubuntu FAMCRU, Cape Town, South Africa.;Tygerberg Hosp, Cape Town, South Africa..
    Hesseling, Anneke C.
    Stellenbosch Univ, Dept Paediat & Child Hlth, Desmond Tutu TB Ctr, Fac Med & Hlth Sci, Cape Town, South Africa..
    van der Laan, Louvina E.
    Univ Cape Town, Div Clin Pharmacol, Dept Med, Cape Town, South Africa.;Stellenbosch Univ, Dept Paediat & Child Hlth, Desmond Tutu TB Ctr, Fac Med & Hlth Sci, Cape Town, South Africa..
    Gonzalez-Martinez, Carmen
    Malawi Liverpool Wellcome Trust Clin Res Programm, Blantyre, Malawi.;Univ Liverpool Liverpool Sch Trop Med, Liverpool, Merseyside, England..
    Zar, Heather J.
    Univ Cape Town, Red Cross War Mem Childrens Hosp, Dept Paediat & Child Hlth, Cape Town, South Africa.;Univ Cape Town, SAMRC Unit Child & Adolescent Hlth, Cape Town, South Africa..
    Davies, Gerry
    Univ Liverpool, Inst Translat Med, Dept Mol & Clin Pharmacol, Liverpool, Merseyside, England.;Univ Liverpool, Inst Infect & Global Hlth, Dept Clin Infect Microbiol & Immunol, Liverpool, Merseyside, England..
    Wiesner, Lubbe
    Univ Cape Town, Div Clin Pharmacol, Dept Med, Cape Town, South Africa..
    Svensson, Elin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Radboud Univ Nijmegen, Radboud Inst Hlth Sci, Dept Pharm, Med Ctr, Nijmegen, Netherlands.;Uppsala Univ, Dept Pharm, Uppsala, Sweden..
    McIlleron, Helen M.
    Univ Cape Town, Div Clin Pharmacol, Dept Med, Cape Town, South Africa.;Univ Cape Town, Inst Infect Dis & Mol Med, Wellcome Ctr Infect Dis Res Africa CIDRI Africa, Cape Town, South Africa..
    Optimizing Dosing and Fixed-Dose Combinations of Rifampicin, Isoniazid, and Pyrazinamide in Pediatric Patients With Tuberculosis: A Prospective Population Pharmacokinetic Study2022In: Clinical Infectious Diseases, ISSN 1058-4838, E-ISSN 1537-6591, Vol. 75, no 1, p. 141-151Article in journal (Refereed)
    Abstract [en]

    Background In 2010, the World Health Organization (WHO) revised dosing guidelines for treatment of childhood tuberculosis. Our aim was to investigate first-line antituberculosis drug exposures under these guidelines, explore dose optimization using the current dispersible fixed-dose combination (FDC) tablet of rifampicin/isoniazid/pyrazinamide; 75/50/150 mg, and suggest a new FDC with revised weight bands. Methods Children with drug-susceptible tuberculosis in Malawi and South Africa underwent pharmacokinetic sampling while receiving first-line tuberculosis drugs as single formulations according the 2010 WHO recommended doses. Nonlinear mixed-effects modeling and simulation was used to design the optimal FDC and weight-band dosing strategy for achieving the pharmacokinetic targets based on literature-derived adult AUC(0-24h) for rifampicin (38.7-72.9), isoniazid (11.6-26.3), and pyrazinamide (233-429 mg center dot h/L). Results In total, 180 children (42% female; 13.9% living with human immunodeficiency virus [HIV]; median [range] age 1.9 [0.22-12] years; weight 10.7 [3.20-28.8] kg) were administered 1, 2, 3, or 4 FDC tablets (rifampicin/isoniazid/pyrazinamide 75/50/150 mg) daily for 4-8, 8-12, 12-16, and 16-25 kg weight bands, respectively. Rifampicin exposure (for weight and age) was up to 50% lower than in adults. Increasing the tablet number resulted in adequate rifampicin but relatively high isoniazid and pyrazinamide exposures. Administering 1, 2, 3, or 4 optimized FDC tablets (rifampicin/isoniazid/pyrazinamide 120/35/130 mg) to children < 6, 6-13, 13-20. and 20-25 kg, and 0.5 tablet in < 3-month-olds with immature metabolism, improved exposures to all 3 drugs. Conclusions Current pediatric FDC doses resulted in low rifampicin exposures. Optimal dosing of all drugs cannot be achieved with the current FDCs. We propose a new FDC formulation and revised weight bands. Current pediatric dosing guidelines lead to infant rifampicin exposures much lower than in adults, whereas isoniazid and pyrazinamide exposures are similar. A new fixed-dose combination (FDC) with rifampicin/isoniazid/pyrazinamide 120/35/130 mg and weight bands of < 6, 6-13, 13-20, and 20-25 kg could improve treatment.

  • 18.
    Diaz, Jessica M. Aguilar
    et al.
    Radboud Univ Nijmegen, Med Ctr, Radboudumc Ctr Infect Dis, TB Expert Ctr Dekkerswald,Dept Pulm Dis, Nijmegen, Netherlands..
    Abulfathi, Ahmed A.
    Univ Florida, Ctr Pharmacometr & Syst Pharmacol, Dept Pharmaceut, Gainesville, FL USA.;Univ Maiduguri, Coll Med Sci, Fac Basic Clin Sci, Dept Clin Pharmacol & Therapeut, Maiduguri, Nigeria.;Stellenbosch Univ, Fac Med & Hlth Sci, Dept Med, Div Clin Pharmacol, Cape Town, South Africa..
    te Brake, Lindsey H. M.
    Radboud Univ Nijmegen, Med Ctr, Radboudumc Ctr Infect Dis, Radboud Inst Hlth Sci,Dept Pharm, Nijmegen, Netherlands..
    van Ingen, Jakko
    Radboud Univ Nijmegen, Med Ctr, Radboudumc Ctr Infect Dis, Dept Med Microbiol, Nijmegen, Netherlands..
    Kuipers, Saskia
    Radboud Univ Nijmegen, Med Ctr, Radboudumc Ctr Infect Dis, Dept Med Microbiol, Nijmegen, Netherlands..
    Magis-Escurra, Cecile
    Radboud Univ Nijmegen, Med Ctr, Radboudumc Ctr Infect Dis, TB Expert Ctr Dekkerswald,Dept Pulm Dis, Nijmegen, Netherlands..
    Raaijmakers, Jelmer
    Radboud Univ Nijmegen, Med Ctr, Radboudumc Ctr Infect Dis, Dept Med Microbiol, Nijmegen, Netherlands..
    Svensson, Elin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Radboud Univ Nijmegen, Med Ctr, Radboudumc Ctr Infect Dis, Radboud Inst Hlth Sci,Dept Pharm, Nijmegen, Netherlands..
    Boeree, Martin J.
    Radboud Univ Nijmegen, Med Ctr, Radboudumc Ctr Infect Dis, TB Expert Ctr Dekkerswald,Dept Pulm Dis, Nijmegen, Netherlands..
    New and Repurposed Drugs for the Treatment of Active Tuberculosis: An Update for Clinicians2023In: Respiration, ISSN 0025-7931, E-ISSN 1423-0356, Vol. 102, no 2, p. 83-100Article, review/survey (Refereed)
    Abstract [en]

    Although tuberculosis (TB) is preventable and curable, the lengthy treatment (generally 6 months), poor patient adherence, high inter-individual variability in pharmacokinetics (PK), emergence of drug resistance, presence of comorbidities, and adverse drug reactions complicate TB therapy and drive the need for new drugs and/or regimens. Hence, new compounds are being developed, available drugs are repurposed, and the dosing of existing drugs is optimized, resulting in the largest drug development portfolio in TB history. This review highlights a selection of clinically available drug candidates that could be part of future TB regimens, including bedaquiline, delamanid, pretomanid, linezolid, clofazimine, optimized (high dose) rifampicin, rifapentine, and para-aminosalicylic acid. The review covers drug development history, preclinical data, PK, and current clinical development.

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  • 19.
    Dierig, A.
    et al.
    LMU Univ Hosp Munich, Div Infect Dis & Trop Med, Munich, Germany.;German Ctr Infect Res DZ, Munich Partner Site, Munich, Germany..
    Hoelscher, M.
    LMU Univ Hosp Munich, Div Infect Dis & Trop Med, Munich, Germany.;German Ctr Infect Res DZ, Munich Partner Site, Munich, Germany..
    Schultz, S.
    LMU Univ Hosp Munich, Div Infect Dis & Trop Med, Munich, Germany.;German Ctr Infect Res DZ, Munich Partner Site, Munich, Germany..
    Hoffmann, L.
    LMU Univ Hosp Munich, Div Infect Dis & Trop Med, Munich, Germany.;German Ctr Infect Res DZ, Munich Partner Site, Munich, Germany..
    Jarchow-MacDonald, A.
    LMU Univ Hosp Munich, Div Infect Dis & Trop Med, Munich, Germany.;German Ctr Infect Res DZ, Munich Partner Site, Munich, Germany.;NHS Tayside, Ninewells Hosp & Med Sch, Dundee, Scotland..
    Svensson, Elin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Radboud Univ Nijmegen, Dept Pharm, Med Ctr, Nijmegen, Netherlands..
    Te Brake, L.
    Radboud Univ Nijmegen, Dept Pharm, Med Ctr, Nijmegen, Netherlands..
    Aarnoutse, R.
    Radboud Univ Nijmegen, Dept Pharm, Med Ctr, Nijmegen, Netherlands..
    Boeree, M.
    Radboud Univ Nijmegen, Dept Pharm, Med Ctr, Nijmegen, Netherlands..
    McHugh, T. D.
    UCL, UCL Ctr Clin Microbiol, Div Infect & Immun, London, England..
    Wildner, L. M.
    UCL, UCL Ctr Clin Microbiol, Div Infect & Immun, London, England..
    Gong, X.
    Univ Calif San Francisco, Dept Med, Div Pulm & Crit Care Med, San Francisco, CA USA..
    Phillips, P. P. J.
    Univ Calif San Francisco, Dept Med, Div Pulm & Crit Care Med, San Francisco, CA USA..
    Minja, L. T.
    Mbeya Med Res Ctr NIMR MMRC, Natl Inst Med Res, Mbeya, Tanzania..
    Ntinginya, N.
    Mbeya Med Res Ctr NIMR MMRC, Natl Inst Med Res, Mbeya, Tanzania..
    Mpagama, S.
    Kilimanjaro Clin Res Inst, Kilimanjaro, Tanzania..
    Liyoyo, A.
    Kilimanjaro Clin Res Inst, Kilimanjaro, Tanzania..
    Wallis, R. S.
    Aurum Inst, Tembisa, South Africa..
    Sebe, M.
    Aurum Inst, Tembisa, South Africa..
    Mhimbira, F. A.
    Ifakara Hlth Inst, Dar Es Salaam, Tanzania..
    Mbeya, B.
    Ifakara Hlth Inst, Dar Es Salaam, Tanzania..
    Rassool, M.
    Univ Witwatersrand, Helen Joseph Hosp, Fac Hlth Sci, Sch Clin Med,Dept Internal Med,Clin HIV Res Unit, Johannesburg, South Africa..
    Geiter, L.
    LegoChem Biosci, Daejeon, South Korea..
    Cho, Y. L.
    LegoChem Biosci, Daejeon, South Korea..
    Heinrich, N.
    LMU Univ Hosp Munich, Div Infect Dis & Trop Med, Munich, Germany.;German Ctr Infect Res DZ, Munich Partner Site, Munich, Germany..
    A phase IIb, open-label, randomized controlled dose ranging multi-centre trial to evaluate the safety, tolerability, pharmacokinetics and exposure-response relationship of different doses of delpazolid in combination with bedaquiline delamanid moxifloxacin in adult subjects with newly diagnosed, uncomplicated, smear-positive, drug-sensitive pulmonary tuberculosis2023In: Trials, E-ISSN 1745-6215, Vol. 24, no 1, article id 382Article in journal (Refereed)
    Abstract [en]

    Background: Linezolid is an effective, but toxic anti-tuberculosis drug that is currently recommended for the treatment of drug-resistant tuberculosis. Improved oxazolidinones should have a better safety profile, while preserving efficacy. Delpazolid is a novel oxazolidinone developed by LegoChem Biosciences Inc. that has been evaluated up to phase 2a clinical trials. Since oxazolidinone toxicity can occur late in treatment, LegoChem Biosciences Inc. and the PanACEA Consortium designed DECODE to be an innovative dose-ranging study with long-term follow-up for determining the exposure-response and exposure-toxicity relationship of delpazolid to support dose selection for later studies. Delpazolid is administered in combination with bedaquiline, delamanid and moxifloxacin.

    Methods: Seventy-five participants with drug-sensitive, pulmonary tuberculosis will receive bedaquiline, delamanid and moxifloxacin, and will be randomized to delpazolid dosages of 0 mg, 400 mg, 800 mg, 1200 mg once daily, or 800 mg twice daily, for 16 weeks. The primary efficacy endpoint will be the rate of decline of bacterial load on treatment, measured by MGIT liquid culture time to detection from weekly sputum cultures. The primary safety endpoint will be the proportion of oxazolidinone class toxicities; neuropathy, myelosuppression, or tyramine pressor response. Participants who convert to negative liquid media culture by week 8 will stop treatment after the end of their 16-week course and will be observed for relapse until week 52. Participants who do not convert to negative culture will receive continuation phase treatment with rifampicin and isoniazid to complete a six-month treatment course.

    Discussion: DECODE is an innovative dose-finding trial, designed to support exposure-response modelling for safe and effective dose selection. The trial design allows assessment of occurrence of late toxicities as observed with linezolid, which is necessary in clinical evaluation of novel oxazolidinones. The primary efficacy endpoint is the change in bacterial load, an endpoint conventionally used in shorter dose-finding trials. Long-term follow-up after shortened treatment is possible through a safety rule excluding slow-and non-responders from potentially poorly performing dosages.

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    FULLTEXT01
  • 20.
    Gafar, Fajri
    et al.
    Univ Groningen, Groningen Res Inst Pharm, Unit PharmacoTherapy Epidemiol & Econ, Groningen, Netherlands..
    Wasmann, Roeland E.
    Univ Cape Town, Div Clin Pharmacol, Dept Med, Cape Town, South Africa..
    McIlleron, Helen M.
    Univ Cape Town, Div Clin Pharmacol, Dept Med, Cape Town, South Africa.;Univ Cape Town, Inst Infect Dis & Mol Med, Wellcome Ctr Infect Dis Res Africa CIDRI Africa, Cape Town, South Africa..
    Aarnoutse, Rob E.
    Radboud Univ Nijmegen, Radboud Inst Hlth Sci, Dept Pharm, Med Ctr, Nijmegen, Netherlands..
    Schaaf, H. Simon
    Stellenbosch Univ, Dept Paediat & Child Hlth, Desmond Tutu TB Ctr, Fac Med & Hlth Sci, Tygerberg, South Africa..
    Marais, Ben J.
    Childrens Hosp Westmead, Sydney, NSW, Australia.;Univ Sydney, Sydney Inst Infect Dis, Sydney, NSW, Australia..
    Agarwal, Dipti
    Ram Manohar Lohia Inst Med Sci, Dept Paediat, Lucknow, Uttar Pradesh, India..
    Antwi, Sampson
    Komfo Anokye Teaching Hosp, Dept Child Hlth, Kumasi, Ghana.;Kwame Nkrumah Univ Sci & Technol, Sch Med Sci, Dept Child Hlth, Kumasi, Ghana..
    Bang, Nguyen D.
    Pham Ngoc Thach Hosp, Ho Chi Minh City, Vietnam..
    Bekker, Adrie
    Stellenbosch Univ, Dept Paediat & Child Hlth, Desmond Tutu TB Ctr, Fac Med & Hlth Sci, Tygerberg, South Africa..
    Bell, David J.
    NHS Greater Glasgow & Clyde, Infect Dis Unit, Glasgow, Lanark, Scotland..
    Chabala, Chishala
    Univ Cape Town, Div Clin Pharmacol, Dept Med, Cape Town, South Africa.;Univ Zambia, Sch Med, Dept Paediat, Lusaka, Zambia.;Childrens Hosp, Univ Teaching Hosp, Lusaka, Zambia..
    Choo, Louise
    UCL, Med Res Council, Clin Trials Unit, London, England..
    Davies, Geraint R.
    Malawi Liverpool Wellcome Clin Res Programme, Clin Dept, Blantyre, Malawi.;Univ Liverpool, Inst Infect Vet & Ecol Sci, Liverpool, Merseyside, England..
    Day, Jeremy N.
    Univ Oxford, Clin Res Unit, Ho Chi Minh City, Vietnam.;Univ Oxford, Nuffield Dept Med, Ctr Trop Med & Global Hlth, Oxford, England..
    Dayal, Rajeshwar
    Sarojini Naidu Med Coll, Dept Pediat, Agra, Uttar Pradesh, India..
    Denti, Paolo
    Univ Cape Town, Div Clin Pharmacol, Dept Med, Cape Town, South Africa..
    Donald, Peter R.
    Stellenbosch Univ, Dept Paediat & Child Hlth, Desmond Tutu TB Ctr, Fac Med & Hlth Sci, Tygerberg, South Africa..
    Engidawork, Ephrem
    Addis Ababa Univ, Sch Pharm, Dept Pharmacol & Clin Pharm, Coll Hlth Sci, Addis Ababa, Ethiopia..
    Garcia-Prats, Anthony J.
    Stellenbosch Univ, Dept Paediat & Child Hlth, Desmond Tutu TB Ctr, Fac Med & Hlth Sci, Tygerberg, South Africa.;Univ Wisconsin, Sch Med & Publ Hlth, Dept Pediat, Madison, WI USA..
    Gibb, Diana
    UCL, Med Res Council, Clin Trials Unit, London, England..
    Graham, Stephen M.
    Univ Melbourne, Dept Pediat, Melbourne, Vic, Australia.;Royal Childrens Hosp, Murdoch Childrens Res Inst, Melbourne, Vic, Australia.;Int Union TB & Lung Dis, Paris, France..
    Hesseling, Anneke C.
    Stellenbosch Univ, Dept Paediat & Child Hlth, Desmond Tutu TB Ctr, Fac Med & Hlth Sci, Tygerberg, South Africa..
    Heysell, Scott K.
    Univ Virginia, Div Infect Dis & Int Hlth, Charlottesville, VA USA..
    Idris, Misgana I.
    Univ Alabama Birmingham, Dept Biol, Birmingham, AL 35294 USA..
    Kabra, Sushil K.
    All India Inst Med Sci, Dept Pediat, New Delhi, India..
    Kinikar, Aarti
    Johns Hopkins Univ, Byramjee Jeejeebhoy Govt Med Coll, Clinical Res Site, Pune, Maharashtra, India..
    Kumar, Agibothu K. Hemanth
    Indian Council Med Res, Natl Inst Res TB, Chennai, Tamil Nadu, India..
    Kwara, Awewura
    Univ Florida, Emerging Pathogens Inst, Coll Med, Gainesville, FL USA..
    Lodha, Rakesh
    All India Inst Med Sci, Dept Pediat, New Delhi, India..
    Magis-Escurra, Cecile
    Radboud Univ Nijmegen, Med Ctr, TB Expert Ctr, Nijmegen, Netherlands..
    Martinez, Nilza
    Inst Nacl Enfermedades Resp & Ambiente, Asuncion, Paraguay..
    Mathew, Binu S.
    Christian Med Coll & Hosp, Dept Pharmacol & Clin Pharmacol, Vellore, Tamil Nadu, India..
    Mave, Vidya
    Johns Hopkins Univ, Byramjee Jeejeebhoy Govt Med Coll, Clinical Res Site, Pune, Maharashtra, India.;Johns Hopkins Univ, Dept Med & Infect Dis, Baltimore, MD USA..
    Mduma, Estomih
    Haydom Lutheran Hosp, Ctr Global Hlth Res, Haydom, Tanzania..
    Mlotha-Mitole, Rachel
    Queen Elizabeth Cent Hosp, Dept Paediat, Blantyre, Malawi..
    Mpagama, Stellah G.
    Kibongoto Infect Dis Hosp, Sanya Juu, Tanzania..
    Mukherjee, Aparna
    All India Inst Med Sci, Dept Pediat, New Delhi, India..
    Nataprawira, Heda M.
    Univ Padjadjaran, Hasan Sadikin Hosp, Div Paediat Respirol, Dept Child Hlth,Fac Med, Bandung, Indonesia..
    Peloquin, Charles A.
    Univ Florida, Coll Pharm, Gainesville, FL USA..
    Pouplin, Thomas
    Mahidol Univ, Fac Trop Med, Mahidol Oxford Trop Med Res Unit, Bangkok, Thailand..
    Ramachandran, Geetha
    Indian Council Med Res, Natl Inst Res TB, Chennai, Tamil Nadu, India..
    Ranjalkar, Jaya
    Christian Med Coll & Hosp, Dept Pharmacol & Clin Pharmacol, Vellore, Tamil Nadu, India..
    Roy, Vandana
    Maulana Azad Med Coll, Dept Pharmacol, New Delhi, India..
    Ruslami, Rovina
    Univ Padjadjaran, Div Pharmacol & Therapy, Dept Biomed Sci, Fac Med, Bandung, Indonesia..
    Shah, Ira
    Bai Jerbai Wadia Hosp Children, Dept Pediat Infect Dis, Pediat TB Clin, Mumbai, Maharashtra, India..
    Singh, Yatish
    Sarojini Naidu Med Coll, Dept Pediat, Agra, Uttar Pradesh, India..
    Sturkenboom, Marieke G. G.
    Univ Groningen, Univ Med Ctr Groningen, Dept Clin Pharm & Pharmacol, Groningen, Netherlands..
    Svensson, Elin M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Radboud Univ Nijmegen, Radboud Inst Hlth Sci, Dept Pharm, Med Ctr, Nijmegen, Netherlands.
    Swaminathan, Soumya
    Indian Council Med Res, Natl Inst Res TB, Chennai, Tamil Nadu, India.;World Hlth Org, Publ Hlth Div, Geneva, Switzerland..
    Thatte, Urmila
    Seth Gordhandas Sunderdas Med Coll & King Edward, Dept Clin Pharmacol, Mumbai, Maharashtra, India..
    Thee, Stephanie
    Charite Univ Med Berlin, Berlin, Germany.;Free Univ Berlin, Berlin, Germany.;Humboldt Univ, Dept Pediat Resp Med Immunol & Crit Care Med, Berlin, Germany..
    Thomas, Tania A.
    Univ Virginia, Div Infect Dis & Int Hlth, Charlottesville, VA USA..
    Tikiso, Tjokosela
    Univ Cape Town, Div Clin Pharmacol, Dept Med, Cape Town, South Africa..
    Touw, Daan J.
    Univ Groningen, Univ Med Ctr Groningen, Dept Clin Pharm & Pharmacol, Groningen, Netherlands..
    Turkova, Anna
    UCL, Med Res Council, Clin Trials Unit, London, England..
    Velpandian, Thirumurthy
    All India Inst Med Sci, Dr RP Ctr, Ocular Pharmacol & Pharm Div, New Delhi, India..
    Verhagen, Lilly M.
    Radboud Univ Nijmegen, Med Ctr, Radboud Ctr Infect Dis, Lab Med Immunol,Sect Pediat Infect Dis, Nijmegen, Netherlands.;Radboud Univ Nijmegen, Med Ctr, Amalia Childrens Hosp, Dept Paediat Infect Dis & Immunol, Nijmegen, Netherlands.;Stellenbosch Univ, Family Ctr Res, UBUNTU, Dept Paediat & Child Hlth, Cape Town, South Africa..
    Winckler, Jana L.
    Stellenbosch Univ, Dept Paediat & Child Hlth, Desmond Tutu TB Ctr, Fac Med & Hlth Sci, Tygerberg, South Africa..
    Yang, Hongmei
    Univ Rochester, Sch Med & Dent, Dept Biostat & Computat Biol, Rochester, NY USA..
    Yunivita, Vycke
    Univ Padjadjaran, Div Pharmacol & Therapy, Dept Biomed Sci, Fac Med, Bandung, Indonesia..
    Taxis, Katja
    Univ Groningen, Groningen Res Inst Pharm, Unit PharmacoTherapy Epidemiol & Econ, Groningen, Netherlands..
    Stevens, Jasper
    Univ Groningen, Univ Med Ctr Groningen, Dept Clin Pharm & Pharmacol, Groningen, Netherlands..
    Alffenaar, Jan-Willem C.
    Univ Sydney, Sydney Inst Infect Dis, Sydney, NSW, Australia.;Univ Sydney, Sch Pharm, Fac Med & Hlth, Sydney, NSW, Australia.;Westmead Hosp, Sydney, NSW, Australia..
    Global estimates and determinants of antituberculosis drug pharmacokinetics in children and adolescents: a systematic review and individual patient data meta-analysis2023In: European Respiratory Journal, ISSN 0903-1936, E-ISSN 1399-3003, Vol. 61, no 3, article id 2201596Article, review/survey (Refereed)
    Abstract [en]

    Background Suboptimal exposure to antituberculosis (anti-TB) drugs has been associated with unfavourable treatment outcomes. We aimed to investigate estimates and determinants of first-line anti-TB drug pharmacokinetics in children and adolescents at a global level.

    Methods We systematically searched MEDLINE, Embase and Web of Science (1990–2021) for pharmacokinetic studies of first-line anti-TB drugs in children and adolescents. Individual patient data were obtained from authors of eligible studies. Summary estimates of total/extrapolated area under the plasma concentration–time curve from 0 to 24 h post-dose (AUC0–24) and peak plasma concentration (Cmax) were assessed with random-effects models, normalised with current World Health Organization-recommended paediatric doses. Determinants of AUC0–24 and Cmax were assessed with linear mixed-effects models.

    Results Of 55 eligible studies, individual patient data were available for 39 (71%), including 1628 participants from 12 countries. Geometric means of steady-state AUC0–24 were summarised for isoniazid (18.7 (95% CI 15.5–22.6) h·mg·L−1), rifampicin (34.4 (95% CI 29.4–40.3) h·mg·L−1), pyrazinamide (375.0 (95% CI 339.9–413.7) h·mg·L−1) and ethambutol (8.0 (95% CI 6.4–10.0) h·mg·L−1). Our multivariate models indicated that younger age (especially <2 years) and HIV-positive status were associated with lower AUC0–24 for all first-line anti-TB drugs, while severe malnutrition was associated with lower AUC0–24 for isoniazid and pyrazinamide. N-acetyltransferase 2 rapid acetylators had lower isoniazid AUC0–24 and slow acetylators had higher isoniazid AUC0–24 than intermediate acetylators. Determinants of Cmax were generally similar to those for AUC0–24.

    Conclusions This study provides the most comprehensive estimates of plasma exposures to first-line anti-TB drugs in children and adolescents. Key determinants of drug exposures were identified. These may be relevant for population-specific dose adjustment or individualised therapeutic drug monitoring.

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  • 21.
    Garcia-Prats, Anthony J.
    et al.
    Univ Wisconsin, Sch Med & Publ Hlth, Dept Pediat, Madison, WI 53705 USA.;Stellenbosch Univ, Fac Med & Hlth Sci, Desmond Tutu TB Ctr, Dept Paediatics & Child Hlth, Cape Town, South Africa..
    Hoddinott, Graeme
    Stellenbosch Univ, Fac Med & Hlth Sci, Desmond Tutu TB Ctr, Dept Paediatics & Child Hlth, Cape Town, South Africa..
    Howell, Pauline
    Univ Witwatersrand, Sizwe Trop Dis Hosp, Dept Internal Med, Clin HIV Res Unit,Wits Hlth Consortium, Johannesburg, South Africa..
    Hughes, Jennifer
    Stellenbosch Univ, Fac Med & Hlth Sci, Desmond Tutu TB Ctr, Dept Paediatics & Child Hlth, Cape Town, South Africa..
    Jean-Philippe, Patrick
    NIAID, NIH, Bethesda, MD USA..
    Kim, Soyeon
    Frontier Sci Fdn, Dept Biostat, Brookline, MA USA..
    Palmer, Megan
    Stellenbosch Univ, Fac Med & Hlth Sci, Desmond Tutu TB Ctr, Dept Paediatics & Child Hlth, Cape Town, South Africa..
    Schaaf, H. Simon
    Stellenbosch Univ, Fac Med & Hlth Sci, Desmond Tutu TB Ctr, Dept Paediatics & Child Hlth, Cape Town, South Africa..
    Seddon, James A.
    Stellenbosch Univ, Fac Med & Hlth Sci, Desmond Tutu TB Ctr, Dept Paediatics & Child Hlth, Cape Town, South Africa.;Imperial Coll London, Dept Infect Dis, London, England..
    Svensson, Elin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Radboud Univ Nijmegen, Med Ctr, Res Inst Med Innovat, Dept Pharm, Nijmegen, Netherlands..
    Hesseling, Anneke C.
    Stellenbosch Univ, Fac Med & Hlth Sci, Desmond Tutu TB Ctr, Dept Paediatics & Child Hlth, Cape Town, South Africa..
    Children deserve simple, short, safe, and effective treatment for rifampicin-resistant tuberculosis2023In: The Lancet - Infectious diseases, ISSN 1473-3099, E-ISSN 1474-4457, Vol. 23, no 7, p. 778-780Article in journal (Other academic)
  • 22.
    Garcia-Prats, Anthony J.
    et al.
    Stellenbosch Univ, Fac Med & Hlth Sci, Desmond Tutu TB Ctr, Dept Paediat & Child Hlth, POB 241, ZA-8000 Cape Town, South Africa.;Univ Wisconsin, Dept Pediat, Sch Med & Publ Hlth, 2870 Univ Ave,Suite 200, Madison, WI 53705 USA..
    Svensson, Elin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Radboud Univ Nijmegen Med Ctr, Radboud Inst Hlth Sci, Dept Pharm, POB 9101, NL-6500 HB Nijmegen, Netherlands..
    Winckler, Jana
    Stellenbosch Univ, Fac Med & Hlth Sci, Desmond Tutu TB Ctr, Dept Paediat & Child Hlth, POB 241, ZA-8000 Cape Town, South Africa..
    Draper, Heather R.
    Stellenbosch Univ, Fac Med & Hlth Sci, Desmond Tutu TB Ctr, Dept Paediat & Child Hlth, POB 241, ZA-8000 Cape Town, South Africa..
    Fairlie, Lee
    Univ Witwatersrand, Fac Hlth Sci, Wits Reprod Hlth & HIV Inst Shandukani CRS, 22 Esselen St, ZA-2001 Hilbrow, South Africa..
    van der Laan, Louvina E.
    Stellenbosch Univ, Fac Med & Hlth Sci, Desmond Tutu TB Ctr, Dept Paediat & Child Hlth, POB 241, ZA-8000 Cape Town, South Africa..
    Masenya, Masebole
    Univ Witwatersrand, Fac Hlth Sci, Wits Reprod Hlth & HIV Inst Shandukani CRS, 22 Esselen St, ZA-2001 Hilbrow, South Africa..
    Schaaf, H. Simon
    Stellenbosch Univ, Fac Med & Hlth Sci, Desmond Tutu TB Ctr, Dept Paediat & Child Hlth, POB 241, ZA-8000 Cape Town, South Africa..
    Wiesner, Lubbe
    Univ Cape Town, Groote Schuur Hosp, Dept Med, Div Clin Pharmacol, K45 Old Main Bldg, ZA-7925 Cape Town, South Africa..
    Norman, Jennifer
    Univ Cape Town, Groote Schuur Hosp, Dept Med, Div Clin Pharmacol, K45 Old Main Bldg, ZA-7925 Cape Town, South Africa..
    Aarnoutse, Rob E.
    Radboud Univ Nijmegen Med Ctr, Radboud Inst Hlth Sci, Dept Pharm, POB 9101, NL-6500 HB Nijmegen, Netherlands..
    Karlsson, Mats O.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Denti, Paolo
    Univ Cape Town, Groote Schuur Hosp, Dept Med, Div Clin Pharmacol, K45 Old Main Bldg, ZA-7925 Cape Town, South Africa..
    Hesseling, Anneke C.
    Stellenbosch Univ, Fac Med & Hlth Sci, Desmond Tutu TB Ctr, Dept Paediat & Child Hlth, POB 241, ZA-8000 Cape Town, South Africa..
    Pharmacokinetics and safety of high-dose rifampicin in children with TB: the Opti-Rif trial2021In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 76, no 12, p. 3237-3246Article in journal (Refereed)
    Abstract [en]

    Background: Rifampicin doses of 40 mg/kg in adults are safe and well tolerated, may shorten anti-TB treatment and improve outcomes, but have not been evaluated in children. Objectives: To characterize the pharmacokinetics and safety of high rifampicin doses in children with drug-susceptible TB. Patients and methods: The Opti-Rif trial enrolled dosing cohorts of 20 children aged 0-12 years, with incremental dose escalation with each subsequent cohort, until achievement of target exposures or safety concerns. Cohort 1 opened with a rifampicin dose of 15 mg/kg for 14 days, with a single higher dose (35 mg/kg) on day 15. Pharmacokinetic data from days 14 and 15 were analysed using population modelling and safety data reviewed. Incrementally increased rifampicin doses for the next cohort (days 1-14 and day 15) were simulated from the updated model, up to the dose expected to achieve the target exposure [235 mg/L.h, the geometric mean area under the concentration-time curve from 0 to 24h (AUC(0-24)) among adults receiving a 35mg/kg dose]. Results: Sixty-two children were enrolled in three cohorts. The median age overall was 2.1 years (range=0.4-11.7). Evaluated doses were similar to 35 mg/kg (days 1-14) and similar to 50 mg/kg (day 15) for cohort 2 and similar to 60 mg/kg (days 1-14) and similar to 75mg/kg (day 15) for cohort 3. Approximately half of participants had an adverse event related to study rifampicin; none was grade 3 or higher. A 65-70 mg/kg rifampicin dose was needed in children to reach the target exposure. Conclusions: High rifampicin doses in children achieved target exposures and the doses evaluated were safe over 2 weeks.

  • 23.
    Haas, David W.
    et al.
    Vanderbilt Univ, Sch Med, Dept Med, Nashville, TN USA.;Meharry Med Coll, Dept Internal Med, Nashville, TN USA.
    Abdelwahab, Mahmoud Tareq
    Univ Cape Town, Dept Med, Div Clin Pharmacol, Cape Town, South Africa.
    van Beek, Stijn W.
    Radboud Univ Nijmegen Med Ctr, Radboud Inst Hlth Sci, Dept Pharm, Nijmegen, Netherlands.
    Baker, Paxton
    Vanderbilt Univ, Med Ctr, Vanderbilt Technol Adv Genom, Nashville, TN USA.
    Maartens, Gary
    Univ Cape Town, Dept Med, Div Clin Pharmacol, Cape Town, South Africa.
    Bradford, Yuki
    Univ Penn, Dept Genet, Philadelphia, PA USA.
    Ritchie, Marylyn D.
    Univ Penn, Dept Genet, Perelman Sch Med, Philadelphia, PA USA.;Univ Penn, Inst Biomed Informat, Perelman Sch Med, Philadelphia, PA USA.
    Wasserman, Sean
    Univ Cape Town, Dept Med, Div Infect Dis, Cape Town, South Africa.
    Meintjes, Graeme
    Univ Cape Town, Wellcome Ctr Infect Dis Res Africa, Inst Infect Dis & Mol Med, Cape Town, South Africa.;Univ Cape Town, Dept Med, Cape Town, South Africa.
    Beeri, Karen
    Vanderbilt Univ, Med Ctr, Vanderbilt Technol Adv Genom, Nashville, TN USA.
    Gandhi, Neel R.
    Emory Univ, Dept Epidemiol, Rollins Sch Publ Hlth, Atlanta, GA USA.;Emory Univ, Dept Global Hlth, Rollins Sch Publ Hlth, Atlanta, GA USA.;Emory Univ, Emory Sch Med, Dept Med, Div Infect Dis, Atlanta, GA USA.
    Svensson, Elin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Radboud Univ Nijmegen Med Ctr, Radboud Inst Hlth Sci, Dept Pharm, Nijmegen, Netherlands.
    Denti, Paolo
    Univ Cape Town, Dept Med, Div Clin Pharmacol, Cape Town, South Africa.
    Brust, James C. M.
    Albert Einstein Coll Med, Dept Med, Div Gen Internal Med, Bronx, NY USA.
    Pharmacogenetics of Between-Individual Variability in Plasma Clearance of Bedaquiline and Clofazimine in South Africa2022In: Journal of Infectious Diseases, ISSN 0022-1899, E-ISSN 1537-6613, Vol. 226, no 1, p. 147-156Article in journal (Refereed)
    Abstract [en]

    In a cohort of patients treated for drug-resistant tuberculosis in South Africa, CYP3A5*3was associated with slower plasma bedaquiline clearance. Different CYP3A5*3minor allele frequencies among populations may help explain the more rapid bedaquiline clearance previously reported with African ancestry.

    Background Plasma bedaquiline clearance is reportedly more rapid with African ancestry. Our objective was to determine whether genetic polymorphisms explained between-individual variability in plasma clearance of bedaquiline, its M2 metabolite, and clofazimine in a cohort of patients treated for drug-resistant tuberculosis in South Africa.

    Methods Plasma clearance was estimated with nonlinear mixed-effects modeling. Associations between pharmacogenetic polymorphisms, genome-wide polymorphisms, and variability in clearance were examined using linear regression models.

    Results Of 195 cohort participants, 140 were evaluable for genetic associations. Among 21 polymorphisms selected based on prior genome-wide significant associations with any drug, rs776746 (CYP3A5*3) was associated with slower clearance of bedaquiline (P = .0017) but not M2 (P = .25). CYP3A5*3 heterozygosity and homozygosity were associated with 15% and 30% slower bedaquiline clearance, respectively. The lowest P value for clofazimine clearance was with VKORC1 rs9923231 (P = .13). In genome-wide analyses, the lowest P values for clearance of bedaquiline and clofazimine were with RFX4 rs76345012 (P = 6.4 x 10(-7)) and CNTN5 rs75285763 (P = 2.9 x 10(-8)), respectively.

    Conclusions Among South Africans treated for drug-resistant tuberculosis, CYP3A5*3 was associated with slower bedaquiline clearance. Different CYP3A5*3 frequencies among populations may help explain the more rapid bedaquiline clearance reported in Africans. Associations with RFX4 and CNTN5 are likely by chance alone.

  • 24.
    Hennig, Stefanie
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Svensson, Elin M
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Niebecker, Ronald
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Fourie, P Bernard
    Weiner, Marc H
    Bonora, Stefano
    Peloquin, Charles A
    Gallicano, Keith
    Flexner, Charles
    Pym, Alex
    Vis, Peter
    Olliaro, Piero L
    McIlleron, Helen
    Karlsson, Mats O
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Population pharmacokinetic drug-drug interaction pooled analysis of existing data for rifabutin and HIV PIs2016In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 71, no 5, p. 1330-1340Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: Extensive but fragmented data from existing studies were used to describe the drug-drug interaction between rifabutin and HIV PIs and predict doses achieving recommended therapeutic exposure for rifabutin in patients with HIV-associated TB, with concurrently administered PIs.

    METHODS: Individual-level data from 13 published studies were pooled and a population analysis approach was used to develop a pharmacokinetic model for rifabutin, its main active metabolite 25-O-desacetyl rifabutin (des-rifabutin) and drug-drug interaction with PIs in healthy volunteers and patients who had HIV and TB (TB/HIV).

    RESULTS: Key parameters of rifabutin affected by drug-drug interaction in TB/HIV were clearance to routes other than des-rifabutin (reduced by 76%-100%), formation of the metabolite (increased by 224% in patients), volume of distribution (increased by 606%) and distribution to the peripheral compartment (reduced by 47%). For des-rifabutin, clearance was reduced by 35%-76% and volume of distribution increased by 67%-240% in TB/HIV. These changes resulted in overall increased exposure to rifabutin in TB/HIV patients by 210% because of the effects of PIs and 280% with ritonavir-boosted PIs.

    CONCLUSIONS: Given together with non-boosted or ritonavir-boosted PIs, rifabutin at 150 mg once daily results in similar or higher exposure compared with rifabutin at 300 mg once daily without concomitant PIs and may achieve peak concentrations within an acceptable therapeutic range. Although 300 mg of rifabutin every 3 days with boosted PI achieves an average equivalent exposure, intermittent doses of rifamycins are not supported by current guidelines.

  • 25.
    Jacobs, Tom G.
    et al.
    Radboud Univ Nijmegen, Radboud Inst Hlth Sci, Med Ctr, Dept Pharm, Nijmegen, Netherlands..
    Svensson, Elin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Radboud Univ Nijmegen, Radboud Inst Hlth Sci, Med Ctr, Dept Pharm, Nijmegen, Netherlands.
    Musiime, Victor
    Joint Clin Res Ctr, Res Dept, Kampala, Uganda.;Makerere Univ, Coll Hlth Sci, Sch Med, Dept Paediat & Child Hlth, Kampala, Uganda..
    Rojo, Pablo
    Univ Complutense, Hosp 12 Octubre, Fac Med, Pediat Infect Dis Unit, Madrid, Spain..
    Dooley, Kelly E.
    Johns Hopkins Univ, Sch Med, Dept Med, Div Clin Pharmacol, Baltimore, MD 21205 USA.;Johns Hopkins Univ, Sch Med, Dept Med, Div Infect Dis, Baltimore, MD 21205 USA..
    McIlleron, Helen
    Univ Cape Town, Dept Med, Div Clin Pharmacol, Cape Town, South Africa..
    Aarnoutse, Rob E.
    Radboud Univ Nijmegen, Radboud Inst Hlth Sci, Med Ctr, Dept Pharm, Nijmegen, Netherlands..
    Burger, David M.
    Radboud Univ Nijmegen, Radboud Inst Hlth Sci, Med Ctr, Dept Pharm, Nijmegen, Netherlands..
    Turkova, Anna
    UCL, Inst Clin Trials & Methodol, MRC Clin Trials Unit UCL, London, England..
    Colbers, Angela
    Radboud Univ Nijmegen, Radboud Inst Hlth Sci, Med Ctr, Dept Pharm, Nijmegen, Netherlands..
    Pharmacokinetics of antiretroviral and tuberculosis drugs in children with HIV/TB co-infection: a systematic review2020In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 75, no 12, p. 3433-3457Article, review/survey (Refereed)
    Abstract [en]

    Introduction: Management of concomitant use of ART and TB drugs is difficult because of the many drug-drug interactions (DDIs) between the medications. This systematic review provides an overview of the current state of knowledge about the pharmacokinetics (PK) of ART and TB treatment in children with HIV/TB co-infection, and identifies knowledge gaps. Methods: We searched Embase and PubMed, and systematically searched abstract books of relevant conferences, following PRISMA guidelines. Studies not reporting PK parameters, investigating medicines that are not available any Longer or not including children with HIV/TB co-infection were excluded. ALL studies were assessed for quality. Results: In total, 47 studies met the inclusion criteria. No dose adjustments are necessary for efavirenz during concomitant first-Line TB treatment use, but intersubject PK variability was high, especially in children <3 years of age. Super-boosted Lopinavir/ritonavir (ratio 1:1) resulted in adequate Lopinavir trough concentrations during rifampicin co-administration. Double-dosed raltegravir can be given with rifampicin in children >4 weeks old as well as twice-daily dolutegravir (instead of once daily) in children older than 6 years. Exposure to some TB drugs (ethambutol and rifampicin) was reduced in the setting of HIV infection, regardless of ART use. Only Limited PK data of second-Line TB drugs with ART in children who are HIV infected have been published. Conclusions: Whereas integrase inhibitors seem favourable in older children, there are Limited options for ART in young children (<3 years) receiving rifampicin-based TB therapy. The PK of TB drugs in HIV-infected children warrants further research.

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  • 26.
    Keutzer, Lina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    You, Huifang
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Farnoud, Ali
    Helmholtz Munich, Computat Hlth Ctr, D-85764 Neuherberg, Germany..
    Nyberg, Joakim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Wicha, Sebastian G.
    Univ Hamburg, Inst Pharm, Dept Clin Pharm, D-20146 Hamburg, Germany..
    Maher-Edwards, Gareth
    GlaxoSmithKline, Res Clin Pharmacol Modelling & Simulat, London TW8 9GS, England..
    Vlasakakis, Georgios
    GlaxoSmithKline, Res Clin Pharmacol Modelling & Simulat, London TW8 9GS, England..
    Moghaddam, Gita Khalili
    GlaxoSmithKline, Res Clin Pharmacol Modelling & Simulat, London TW8 9GS, England.;Univ Cambridge, Dept Clin Neurosci, Cambridge CB2 0QQ, England..
    Svensson, Elin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Radboud Univ Nijmegen, Radboud Inst Hlth Sci, Dept Pharm, Med Ctr, NL-6525 EZ Nijmegen, Netherlands..
    Menden, Michael P.
    Helmholtz Munich, Computat Hlth Ctr, D-85764 Neuherberg, Germany.;Ludwig Maximilian Univ Munich, Dept Biol, D-82152 Planegg Martinsried, Germany.;German Ctr Diabet Res DZD eV, D-85764 Neuherberg, Germany..
    Simonsson, Ulrika S. H.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Machine Learning and Pharmacometrics for Prediction of Pharmacokinetic Data: Differences, Similarities and Challenges Illustrated with Rifampicin2022In: Pharmaceutics, ISSN 1999-4923, E-ISSN 1999-4923, Vol. 14, no 8, article id 1530Article in journal (Refereed)
    Abstract [en]

    Pharmacometrics (PM) and machine learning (ML) are both valuable for drug development to characterize pharmacokinetics (PK) and pharmacodynamics (PD). Pharmacokinetic/pharmacodynamic (PKPD) analysis using PM provides mechanistic insight into biological processes but is time- and labor-intensive. In contrast, ML models are much quicker trained, but offer less mechanistic insights. The opportunity of using ML predictions of drug PK as input for a PKPD model could strongly accelerate analysis efforts. Here exemplified by rifampicin, a widely used antibiotic, we explore the ability of different ML algorithms to predict drug PK. Based on simulated data, we trained linear regressions (LASSO), Gradient Boosting Machines, XGBoost and Random Forest to predict the plasma concentration-time series and rifampicin area under the concentration-versus-time curve from 0-24 h (AUC(0-24h)) after repeated dosing. XGBoost performed best for prediction of the entire PK series (R-2: 0.84, root mean square error (RMSE): 6.9 mg/L, mean absolute error (MAE): 4.0 mg/L) for the scenario with the largest data size. For AUC(0-24h) prediction, LASSO showed the highest performance (R-2: 0.97, RMSE: 29.1 h center dot mg/L, MAE: 18.8 h center dot mg/L). Increasing the number of plasma concentrations per patient (0, 2 or 6 concentrations per occasion) improved model performance. For example, for AUC(0-24h) prediction using LASSO, the R-2 was 0.41, 0.69 and 0.97 when using predictors only (no plasma concentrations), 2 or 6 plasma concentrations per occasion as input, respectively. Run times for the ML models ranged from 1.0 s to 8 min, while the run time for the PM model was more than 3 h. Furthermore, building a PM model is more time- and labor-intensive compared with ML. ML predictions of drug PK could thus be used as input into a PKPD model, enabling time-efficient analysis.

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  • 27. Koele, Simon E
    et al.
    Dorlo, Thomas P. C.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Upton, Caryn M
    Aarnoutse, Rob E
    Svensson, Elin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Power to identify exposure-response relationships in phase IIa pulmonary tuberculosis trials with multi-dimensional bacterial load modeling.2023In: CPT: Pharmacometrics and Systems Pharmacology (PSP), E-ISSN 2163-8306Article in journal (Refereed)
    Abstract [en]

    Adequate power to identify an exposure-response relationship in a phase IIa clinical trial for pulmonary tuberculosis (TB) is important for dose selection and design of follow-up studies. Currently, it is not known what response marker provides the pharmacokinetic-pharmacodynamic (PK-PD) model more power to identify an exposure-response relationship. We simulated colony-forming units (CFU) and time-to-positivity (TTP) measurements for four hypothetical drugs with different activity profiles for 14 days. The power to identify exposure-response relationships when analyzing CFU, TTP, or combined CFU + TTP data was determined at 60 total participants, or with 25 out of 60 participants in the lowest and highest dosing groups (unbalanced design). For drugs with moderate bactericidal activity, power was low (<59%), irrespective of the data analyzed. Power was 1.9% to 29.4% higher when analyzing TTP data compared to CFU data. Combined analysis of CFU and TTP further improved the power, on average by 4.2%. For a drug with a medium-high activity, the total sample size needed to achieve 80% power was 136 for CFU, 72 for TTP, and 68 for combined CFU + TTP data. The unbalanced design improved the power by 16% over the balanced design. In conclusion, the power to identify an exposure-response relationship is low for TB drugs with moderate bactericidal activity or with a slow onset of activity. TTP provides the PK-PD model with more power to identify exposure-response relationships compared to CFU, and combined analysis or an unbalanced dosing group study design offers modest further improvement.

  • 28.
    Koele, Simon E.
    et al.
    Radboud Univ Nijmegen, Radboud Inst Med Innovat, Med Ctr, Dept Pharm, Nijmegen, Netherlands.;Radboud Univ Nijmegen, Med Ctr, Dept Pharm, POB 9101, NL-6500 HB Nijmegen, Netherlands..
    Phillips, Patrick P. J.
    Univ Calif San Francisco, UCSF Ctr TB, Dept Med, San Francisco, CA USA..
    Upton, Caryn M.
    TASK Appl Sci, Cape Town, South Africa..
    van Ingen, Jakko
    Radboud Univ Nijmegen, Med Ctr, Dept Med Microbiol, Nijmegen, Netherlands..
    Simonsson, Ulrika S. H.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Diacon, Andreas H.
    TASK Appl Sci, Cape Town, South Africa..
    Aarnoutse, Rob E.
    Radboud Univ Nijmegen, Radboud Inst Med Innovat, Med Ctr, Dept Pharm, Nijmegen, Netherlands..
    Svensson, Elin M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Radboud Univ Nijmegen, Radboud Inst Med Innovat, Med Ctr, Dept Pharm, Nijmegen, Netherlands.
    Early bactericidal activity studies for pulmonary tuberculosis: A systematic review of methodological aspects2023In: International Journal of Antimicrobial Agents, ISSN 0924-8579, E-ISSN 1872-7913, Vol. 61, no 5, article id 106775Article, review/survey (Refereed)
    Abstract [en]

    A milestone in the development of novel antituberculosis drugs is the demonstration of early bactericidal activity (EBA) in a phase IIa clinical trial. The significant variability in measurements of bacterial load complicates data analysis in these trials.

    A systematic review and evaluation of methods for determination of EBA in pulmonary tuberculosis studies was undertaken. Bacterial load quantification biomarkers, reporting intervals, calculation methods, statistical testing, and handling of negative culture results were extracted. In total, 79 studies were identi-fied in which EBA was determined. Colony-forming units on solid culture media and/or time-to-positivity in liquid media were the biomarkers used most often, reported in 72 (91%) and 34 (43%) studies, respec-tively. Twenty-two different reporting intervals were presented, and 12 different calculation methods for EBA were identified. Statistical testing for a significant EBA compared with no change was performed in 54 (68%) studies, and between-group testing was performed in 32 (41%) studies. Negative culture result handling was discussed in 34 (43%) studies.

    Notable variation was found in the analysis methods and reporting of EBA studies. A standardized and clearly reported analysis method, accounting for different levels of variability in the data, could aid the generalization of study results and facilitate comparison between drugs/regimens.

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  • 29.
    Koele, Simon E.
    et al.
    Radboud Univ Nijmegen, Radboud Inst Hlth Sci, Dept Pharm, Med Ctr, Nijmegen, Netherlands..
    van Beek, Stijn W.
    Radboud Univ Nijmegen, Radboud Inst Hlth Sci, Dept Pharm, Med Ctr, Nijmegen, Netherlands..
    Maartens, Gary
    Univ Cape Town, Wellcome Ctr Infect Dis Res Africa, Inst Infect Dis & Mol Med, Cape Town, South Africa.;Univ Cape Town, Dept Med, Div Clin Pharmacol, Cape Town, South Africa..
    Brust, James C. M.
    Albert Einstein Coll Med, Div Gen Internal Med, New York, NY USA.;Albert Einstein Coll Med, Div Infect Dis, New York, NY USA..
    Svensson, Elin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Radboud Univ Nijmegen, Radboud Inst Hlth Sci, Dept Pharm, Med Ctr, Nijmegen, Netherlands..
    Optimized Loading Dose Strategies for Bedaquiline When Restarting Interrupted Drug-Resistant Tuberculosis Treatment2022In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 66, no 3, article id e01749-21Article in journal (Refereed)
    Abstract [en]

    Interruption of treatment is common in drug-resistant tuberculosis patients. Bedaquiline has a long terminal half-life; therefore, restarting after an interruption without a loading dose could increase the risk of suboptimal treatment outcome and resistance development. Interruption of treatment is common in drug-resistant tuberculosis patients. Bedaquiline has a long terminal half-life; therefore, restarting after an interruption without a loading dose could increase the risk of suboptimal treatment outcome and resistance development. We aimed to identify the most suitable loading dose strategies for bedaquiline restart after an interruption. A model-based simulation study was performed. Pharmacokinetic profiles of bedaquiline and its metabolite M2 (associated with QT prolongation) were simulated for 5,000 virtual patients for different durations and starting points of treatment interruption. Weekly bedaquiline area under the concentration-time curve (AUC) and M2 maximum concentration (C-max) deviation before interruption and after reloading were assessed to evaluate the efficacy and safety, respectively, of the reloading strategies. Bedaquiline weekly AUC and M2 C-max deviation were mainly driven by the duration of interruption and only marginally by the starting point of interruption. For interruptions with a duration shorter than 2 weeks, no new loading dose is needed. For interruptions with durations between 2 weeks and 1 month, 1 month and 1 year, and longer than 1 year, reloading periods of 3 days, 1 week, and 2 weeks, respectively, are recommended. This reloading strategy results in an average bedaquiline AUC deviation of 1.88% to 5.98% compared with -16.4% to -59.8% without reloading for interruptions of 2 weeks and 1 year, respectively, without increasing M2 C-max. This study presents easy-to-implement reloading strategies for restarting a patient on bedaquiline treatment after an interruption.

  • 30.
    Litjens, Carlijn H. C.
    et al.
    Radboud Univ Nijmegen, Med Ctr, Radboud Inst Hlth Sci, Dept Pharm, Nijmegen, Netherlands;Radboud Univ Nijmegen, Med Ctr, Radboud Inst Hlth Sci, Dept Pharmacol & Toxicol, Nijmegen, Netherlands.
    Aarnoutse, Rob E.
    Radboud Univ Nijmegen, Med Ctr, Radboud Inst Hlth Sci, Dept Pharm, Nijmegen, Netherlands.
    Kolmer, Eleonora W. J. van Ewijk-Beneken
    Radboud Univ Nijmegen, Med Ctr, Radboud Inst Hlth Sci, Dept Pharm, Nijmegen, Netherlands.
    Svensson, Elin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Radboud Univ Nijmegen, Med Ctr, Radboud Inst Hlth Sci, Dept Pharm, Nijmegen, Netherlands.
    Colbers, Angela
    Radboud Univ Nijmegen, Med Ctr, Radboud Inst Hlth Sci, Dept Pharm, Nijmegen, Netherlands.
    Burger, David M.
    Radboud Univ Nijmegen, Med Ctr, Radboud Inst Hlth Sci, Dept Pharm, Nijmegen, Netherlands.
    Boeree, Martin J.
    Radboud Univ Nijmegen, Dept Pulm Dis, Med Ctr, Nijmegen, Netherlands.
    te Brake, Lindsey H. M.
    Radboud Univ Nijmegen, Med Ctr, Radboud Inst Hlth Sci, Dept Pharm, Nijmegen, Netherlands.
    Aarnoutse, Rob
    Boeree, Martin
    Heinrich, Norbert
    Diacon, Andreas
    Dawson, Rodney
    Rehal, Sunita
    Kibiki, Gibson
    Churchyard, Gavin
    Sanne, Ian
    Ntinginya, Nyanda
    Minja, Lilian
    Hunt, Robert
    Charalambous, Salome
    Hanekom, Madeleine
    Semvua, Hadija
    Mpagama, Stellah
    Manyama, Christina
    Mtafya, Bariki
    Reither, Klaus
    Wallis, Robert
    Venter, Amour
    Narunsky, Kim
    Mekota, Anna-Maria
    Henne, Sonja
    van Balen, Georgette Plemper
    Gillespie, Stephen
    Phillips, Patrick
    Hoelscher, Michael
    Protein binding of rifampicin is not saturated when using high-dose rifampicin2019In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 74, no 4, p. 986-990Article in journal (Refereed)
    Abstract [en]

    Background Higher doses of rifampicin are being investigated as a means to optimize response to this pivotal TB drug. It is unknown whether high-dose rifampicin results in saturation of plasma protein binding and a relative increase in protein-unbound (active) drug concentrations. Objectives To assess the free fraction of rifampicin based on an in vitro experiment and data from a clinical trial on high-dose rifampicin. Methods Protein-unbound rifampicin concentrations were measured in human serum spiked with increasing total concentrations (up to 64mg/L) of rifampicin and in samples obtained by intensive pharmacokinetic sampling of patients who used standard (10mg/kg daily) or high-dose (35mg/kg) rifampicin up to steady-state. The performance of total AUC(0-24) to predict unbound AUC(0-24) was evaluated. Results The in vitro free fraction of rifampicin remained unaltered (approximate to 9%) up to 21mg/L and increased up to 13% at 41mg/L and 17% at 64mg/L rifampicin. The highest (peak) concentration in vivo was 39.1mg/L (high-dose group). The arithmetic mean percentage unbound to total AUC(0-24)in vivo was 13.3% (range=8.1%-24.9%) and 11.1% (range=8.6%-13.6%) for the standard group and the high-dose group, respectively (P=0.214). Prediction of unbound AUC(0-24) based on total AUC(0-24) resulted in a bias of -0.05% and an imprecision of 13.2%. Conclusions Plasma protein binding of rifampicin can become saturated, but exposures after high-dose rifampicin are not high enough to increase the free fraction in TB patients with normal albumin values. Unbound rifampicin exposures can be predicted from total exposures, even in the higher dose range.

  • 31.
    Litjens, Carlijn H. C.
    et al.
    Radboud Univ Nijmegen, Radboud Inst Hlth Sci, Dept Pharm, Med Ctr, Nijmegen, Netherlands.;Radboud Univ Nijmegen, Radboudumc Ctr Infect Dis, Med Ctr, Nijmegen, Netherlands.;Radboud Univ Nijmegen, Radboud Inst Mol Life Sci, Dept Pharmacol & Toxicol, Med Ctr, Nijmegen, Netherlands..
    Verscheijden, Laurens F. M.
    Radboud Univ Nijmegen, Radboud Inst Mol Life Sci, Dept Pharmacol & Toxicol, Med Ctr, Nijmegen, Netherlands..
    Bolwerk, Celine
    Radboud Univ Nijmegen, Radboud Inst Hlth Sci, Dept Pharm, Med Ctr, Nijmegen, Netherlands.;Radboud Univ Nijmegen, Radboudumc Ctr Infect Dis, Med Ctr, Nijmegen, Netherlands..
    Greupink, Rick
    Radboud Univ Nijmegen, Radboud Inst Mol Life Sci, Dept Pharmacol & Toxicol, Med Ctr, Nijmegen, Netherlands..
    Koenderink, Jan B.
    Radboud Univ Nijmegen, Radboud Inst Mol Life Sci, Dept Pharmacol & Toxicol, Med Ctr, Nijmegen, Netherlands..
    van den Broek, Petra H. H.
    Radboud Univ Nijmegen, Radboud Inst Mol Life Sci, Dept Pharmacol & Toxicol, Med Ctr, Nijmegen, Netherlands..
    van den Heuvel, Jeroen J. M. W.
    Radboud Univ Nijmegen, Radboud Inst Mol Life Sci, Dept Pharmacol & Toxicol, Med Ctr, Nijmegen, Netherlands..
    Svensson, Elin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Radboud Univ Nijmegen, Radboud Inst Hlth Sci, Dept Pharm, Med Ctr, Nijmegen, Netherlands.;Radboud Univ Nijmegen, Radboudumc Ctr Infect Dis, Med Ctr, Nijmegen, Netherlands..
    Boeree, Martin J.
    Radboud Univ Nijmegen, Radboudumc Ctr Infect Dis, Med Ctr, Nijmegen, Netherlands.;Radboud Univ Nijmegen, Radboud Inst Hlth Sci, Dept Pulm Dis, Med Ctr, Nijmegen, Netherlands..
    Magis-Escurra, Cecile
    Radboud Univ Nijmegen, Radboudumc Ctr Infect Dis, Med Ctr, Nijmegen, Netherlands.;Radboud Univ Nijmegen, Radboud Inst Hlth Sci, Dept Pulm Dis, Med Ctr, Nijmegen, Netherlands..
    Hoefsloot, Wouter
    Radboud Univ Nijmegen, Radboudumc Ctr Infect Dis, Med Ctr, Nijmegen, Netherlands.;Radboud Univ Nijmegen, Radboud Inst Hlth Sci, Dept Pulm Dis, Med Ctr, Nijmegen, Netherlands..
    van Crevel, Reinout
    Radboud Univ Nijmegen, Radboudumc Ctr Infect Dis, Med Ctr, Nijmegen, Netherlands.;Radboud Univ Nijmegen, Radboud Inst Hlth Sci, Dept Internal Med, Med Ctr, Nijmegen, Netherlands..
    van Laarhoven, Arjan
    Radboud Univ Nijmegen, Radboudumc Ctr Infect Dis, Med Ctr, Nijmegen, Netherlands.;Radboud Univ Nijmegen, Radboud Inst Hlth Sci, Dept Internal Med, Med Ctr, Nijmegen, Netherlands..
    van Ingen, Jakko
    Radboud Univ Nijmegen, Radboudumc Ctr Infect Dis, Med Ctr, Nijmegen, Netherlands.;Radboud Univ Nijmegen, Radboud Inst Hlth Sci, Dept Med Microbiol, Med Ctr, Nijmegen, Netherlands..
    Kuipers, Saskia
    Radboud Univ Nijmegen, Radboudumc Ctr Infect Dis, Med Ctr, Nijmegen, Netherlands.;Radboud Univ Nijmegen, Radboud Inst Hlth Sci, Dept Med Microbiol, Med Ctr, Nijmegen, Netherlands..
    Ruslami, Rovina
    Univ Padjadjaran, Fac Med, TB HIV Res Ctr, Bandung, Indonesia.;Univ Padjadjaran, Fac Med, Dept Biomed Sci, Div Pharmacol & Therapy, Bandung, Indonesia..
    Burger, David M.
    Radboud Univ Nijmegen, Radboud Inst Hlth Sci, Dept Pharm, Med Ctr, Nijmegen, Netherlands.;Radboud Univ Nijmegen, Radboudumc Ctr Infect Dis, Med Ctr, Nijmegen, Netherlands..
    Russel, Frans G. M.
    Radboud Univ Nijmegen, Radboud Inst Mol Life Sci, Dept Pharmacol & Toxicol, Med Ctr, Nijmegen, Netherlands..
    Aarnoutse, Rob E.
    Radboud Univ Nijmegen, Radboud Inst Hlth Sci, Dept Pharm, Med Ctr, Nijmegen, Netherlands.;Radboud Univ Nijmegen, Radboudumc Ctr Infect Dis, Med Ctr, Nijmegen, Netherlands..
    Te Brake, Lindsey H. M.
    Radboud Univ Nijmegen, Radboud Inst Hlth Sci, Dept Pharm, Med Ctr, Nijmegen, Netherlands.;Radboud Univ Nijmegen, Radboudumc Ctr Infect Dis, Med Ctr, Nijmegen, Netherlands..
    Prediction of Moxifloxacin Concentrations in Tuberculosis Patient Populations by Physiologically Based Pharmacokinetic Modeling2022In: Journal of clinical pharmacology, ISSN 0091-2700, E-ISSN 1552-4604, Vol. 62, no 3, p. 385-396Article in journal (Refereed)
    Abstract [en]

    Moxifloxacin has an important role in the treatment of tuberculosis (TB). Unfortunately, coadministration with the cornerstone TB drug rifampicin results in suboptimal plasma exposure. We aimed to gain insight into the moxifloxacin pharmacokinetics and the interaction with rifampicin. Moreover, we provided a mechanistic framework to understand moxifloxacin pharmacokinetics. We developed a physiologically based pharmacokinetic model in Simcyp version 19, with available and newly generated in vitro and in vivo data, to estimate pharmacokinetic parameters of moxifloxacin alone and when administered with rifampicin. By combining these strategies, we illustrate that the role of P-glycoprotein in moxifloxacin transport is limited and implicate MRP2 as transporter of moxifloxacin-glucuronide followed by rapid hydrolysis in the gut. Simulations of multiple dose area under the plasma concentration-time curve (AUC) of moxifloxacin (400 mg once daily) with and without rifampicin (600 mg once daily) were in accordance with clinically observed data (predicted/observed [P/O] ratio of 0.87 and 0.80, respectively). Importantly, increasing the moxifloxacin dose to 600 mg restored the plasma exposure both in actual patients with TB as well as in our simulations. Furthermore, we extrapolated the single dose model to pediatric populations (P/O AUC ratios, 1.04-1.52) and the multiple dose model to children with TB (P/O AUC ratio, 1.51). In conclusion, our combined approach resulted in new insights into moxifloxacin pharmacokinetics and accurate simulations of moxifloxacin exposure with and without rifampicin. Finally, various knowledge gaps were identified, which may be considered as avenues for further physiologically based pharmacokinetic refinement.

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  • 32.
    Litjens, Carlijn H. C.
    et al.
    Radboud Univ Nijmegen Med Ctr, Radboud Inst Hlth Sci, Dept Pharm, Geert Grootepl Zuid 10, NL-6525 GA Nijmegen, Netherlands.;Radboud Univ Nijmegen Med Ctr, Radboud Inst Mol Life Sci, Dept Pharmacol & Toxicol, Geert Grootepl Zuid 10, NL-6525 GA Nijmegen, Netherlands..
    Verscheijden, Laurens F. M.
    Radboud Univ Nijmegen Med Ctr, Radboud Inst Mol Life Sci, Dept Pharmacol & Toxicol, Geert Grootepl Zuid 10, NL-6525 GA Nijmegen, Netherlands..
    Svensson, Elin M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Radboud Univ Nijmegen Med Ctr, Radboud Inst Hlth Sci, Dept Pharm, Geert Grootepl Zuid 10, NL-6525 GA Nijmegen, Netherlands..
    van den Broek, Petra H. H.
    Radboud Univ Nijmegen Med Ctr, Radboud Inst Mol Life Sci, Dept Pharmacol & Toxicol, Geert Grootepl Zuid 10, NL-6525 GA Nijmegen, Netherlands..
    van Hove, Hedwig
    Radboud Univ Nijmegen Med Ctr, Radboud Inst Mol Life Sci, Dept Pharmacol & Toxicol, Geert Grootepl Zuid 10, NL-6525 GA Nijmegen, Netherlands..
    Koenderink, Jan B.
    Radboud Univ Nijmegen Med Ctr, Radboud Inst Mol Life Sci, Dept Pharmacol & Toxicol, Geert Grootepl Zuid 10, NL-6525 GA Nijmegen, Netherlands..
    Russel, Frans G. M.
    Radboud Univ Nijmegen Med Ctr, Radboud Inst Mol Life Sci, Dept Pharmacol & Toxicol, Geert Grootepl Zuid 10, NL-6525 GA Nijmegen, Netherlands..
    Aarnoutse, Rob E.
    Radboud Univ Nijmegen Med Ctr, Radboud Inst Hlth Sci, Dept Pharm, Geert Grootepl Zuid 10, NL-6525 GA Nijmegen, Netherlands..
    te Brake, Lindsey H. M.
    Radboud Univ Nijmegen Med Ctr, Radboud Inst Hlth Sci, Dept Pharm, Geert Grootepl Zuid 10, NL-6525 GA Nijmegen, Netherlands..
    Physiologically-Based Pharmacokinetic Modelling to Predict the Pharmacokinetics and Pharmacodynamics of Linezolid in Adults and Children with Tuberculous Meningitis2023In: Antibiotics, ISSN 0066-4774, E-ISSN 2079-6382, Vol. 12, no 4, article id 702Article in journal (Refereed)
    Abstract [en]

    Linezolid is used off-label for treatment of central nervous system infections. However, its pharmacokinetics and target attainment in cranial cerebrospinal fluid (CSF) in tuberculous meningitis patients is unknown. This study aimed to predict linezolid cranial CSF concentrations and assess attainment of pharmacodynamic (PD) thresholds (AUC:MIC of >119) in plasma and cranial CSF of adults and children with tuberculous meningitis. A physiologically based pharmacokinetic (PBPK) model was developed to predict linezolid cranial CSF profiles based on reported plasma concentrations. Simulated steady-state PK curves in plasma and cranial CSF after linezolid doses of 300 mg BID, 600 mg BID, and 1200 mg QD in adults resulted in geometric mean AUC:MIC ratios in plasma of 118, 281, and 262 and mean cranial CSF AUC:MIC ratios of 74, 181, and 166, respectively. In children using similar to 10 mg/kg BID linezolid, AUC:MIC values at steady-state in plasma and cranial CSF were 202 and 135, respectively. Our model predicts that 1200 mg per day in adults, either 600 mg BID or 1200 mg QD, results in reasonable (87%) target attainment in cranial CSF. Target attainment in our simulated paediatric population was moderate (56% in cranial CSF). Our PBPK model can support linezolid dose optimization efforts by simulating target attainment close to the site of TBM disease.

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  • 33.
    Lopez-Varela, Elisa
    et al.
    Stellenbosch Univ, Fac Med & Hlth Sci, Desmond Tutu TB Ctr, Dept Paediat & Child Hlth, Cape Town, South Africa.;Hosp Clin Univ Barcelona, Barcelona Ctr Int Hlth Res CRESIB, ISGlobal, Barcelona, Spain..
    Abulfathi, Ahmed A.
    Stellenbosch Univ, Fac Med & Hlth Sci, Dept Med, Div Clin Pharmacol, Cape Town, South Africa.;Univ Maiduguri, Coll Med Sci, Fac Basic Clin Sci, Dept Clin Pharmacol & Therapeut, Maiduguri, Nigeria.;Univ Florida, Coll Pharm, Ctr Pharmacometr & Syst Pharmacol, Dept Pharmaceut, Orlando, FL USA..
    Strydom, Natasha
    Univ Calif San Francisco, Dept Bioengn & Therapeut Sci, San Francisco, CA 94158 USA..
    Goussard, Pierre
    Stellenbosch Univ, Fac Med & Hlth Sci, Dept Paediat & Child Hlth, Cape Town, South Africa..
    van Wyk, Abraham C.
    Stellenbosch Univ, Tygerberg Hosp, Fac Med & Hlth Sci, Natl Hlth Lab Serv,Div Anat Pathol, Cape Town, South Africa..
    Demers, Anne Marie
    Stellenbosch Univ, Fac Med & Hlth Sci, Desmond Tutu TB Ctr, Dept Paediat & Child Hlth, Cape Town, South Africa.;Ctr Hosp Univ St Justine, Serv Microbiol, Dept Clin Med Lab, Montreal, PQ, Canada..
    Van Deventer, Anneen
    Stellenbosch Univ, Fac Med & Hlth Sci, Desmond Tutu TB Ctr, Dept Paediat & Child Hlth, Cape Town, South Africa..
    Garcia-Prats, Anthony J.
    Stellenbosch Univ, Fac Med & Hlth Sci, Desmond Tutu TB Ctr, Dept Paediat & Child Hlth, Cape Town, South Africa.;Univ Wisconsin, Dept Pediat, Sch Med & Publ Hlth, Madison, WI USA..
    van der Merwe, Johannes
    Stellenbosch Univ, Fac Med & Hlth Sci, Dept Med, Div Clin Pharmacol, Cape Town, South Africa..
    Zimmerman, Matthew
    Hackensack Meridian Hlth, Ctr Discovery & Innovat, Nutley, NJ USA.;Hackensack Sch Med, Dept Med Sci, Nutley, NJ USA..
    Carter, Claire L.
    Hackensack Meridian Hlth, Ctr Discovery & Innovat, Nutley, NJ USA.;Hackensack Sch Med, Dept Med Sci, Nutley, NJ USA.;Hackensack Sch Med, Dept Pathol, Nutley, NJ 07110 USA..
    Janson, Jacques
    Stellenbosch Univ, Fac Med & Hlth Sci, Dept Surg, Div Cardiothorac Surg, Cape Town, South Africa..
    Morrison, Julie
    Stellenbosch Univ, Fac Med & Hlth Sci, Dept Paediat & Child Hlth, Cape Town, South Africa..
    Reuter, Helmuth
    Stellenbosch Univ, Fac Med & Hlth Sci, Dept Med, Div Clin Pharmacol, Cape Town, South Africa..
    Decloedt, Eric H.
    Stellenbosch Univ, Fac Med & Hlth Sci, Dept Med, Div Clin Pharmacol, Cape Town, South Africa..
    Seddon, James A.
    Stellenbosch Univ, Fac Med & Hlth Sci, Desmond Tutu TB Ctr, Dept Paediat & Child Hlth, Cape Town, South Africa.;Imperial Coll London, Dept Infect Dis, London, England..
    Svensson, Elin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Radboud Univ Nijmegen, Radboud Inst Hlth Sci, Dept Pharm, Med Ctr, Nijmegen, Netherlands..
    Warren, Rob
    Stellenbosch Univ, Fac Med & Hlth Sci, DST NRF Ctr Excellence Biomed TB Res, Div Mol Biol & Human Genet,South African Med Res, Cape Town, South Africa..
    Savic, Radojka M.
    Univ Calif San Francisco, Dept Bioengn & Therapeut Sci, San Francisco, CA 94158 USA..
    Dartois, Veronique
    Hackensack Meridian Hlth, Ctr Discovery & Innovat, Nutley, NJ USA.;Hackensack Sch Med, Dept Med Sci, Nutley, NJ USA..
    Hesseling, Anneke C.
    Stellenbosch Univ, Fac Med & Hlth Sci, Desmond Tutu TB Ctr, Dept Paediat & Child Hlth, Cape Town, South Africa..
    Drug concentration at the site of disease in children with pulmonary tuberculosis2022In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 77, no 6, p. 1710-1719Article in journal (Refereed)
    Abstract [en]

    Background Current TB treatment for children is not optimized to provide adequate drug levels in TB lesions. Dose optimization of first-line antituberculosis drugs to increase exposure at the site of disease could facilitate more optimal treatment and future treatment-shortening strategies across the disease spectrum in children with pulmonary TB. Objectives To determine the concentrations of first-line antituberculosis drugs at the site of disease in children with intrathoracic TB. Methods We quantified drug concentrations in tissue samples from 13 children, median age 8.6 months, with complicated forms of pulmonary TB requiring bronchoscopy or transthoracic surgical lymph node decompression in a tertiary hospital in Cape Town, South Africa. Pharmacokinetic models were used to describe drug penetration characteristics and to simulate concentration profiles for bronchoalveolar lavage, homogenized lymph nodes, and cellular and necrotic lymph node lesions. Results Isoniazid, rifampicin and pyrazinamide showed lower penetration in most lymph node areas compared with plasma, while ethambutol accumulated in tissue. None of the drugs studied was able to reach target concentration in necrotic lesions. Conclusions Despite similar penetration characteristics compared with adults, low plasma exposures in children led to low site of disease exposures for all drugs except for isoniazid.

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  • 34.
    Ngwalero, Precious
    et al.
    Univ Cape Town, Dept Med, Div Clin Pharmacol, Cape Town, South Africa..
    Brust, James C. M.
    Albert Einstein Coll Med, Bronx, NY 10467 USA.;Montefiore Med Ctr, 111 E 210th St, Bronx, NY 10467 USA..
    van Beek, Stijn W.
    Radboud Univ Nijmegen, Med Ctr, Radboud Inst Hlth Sci, Dept Pharm, Nijmegen, Netherlands..
    Wasserman, Sean
    Univ Cape Town, Wellcome Ctr Infect Dis Res Africa, Inst Infect Dis & Mol Med, Cape Town, South Africa.;Univ Cape Town, Dept Med, Cape Town, South Africa..
    Maartens, Gary
    Univ Cape Town, Dept Med, Div Clin Pharmacol, Cape Town, South Africa.;Univ Cape Town, Wellcome Ctr Infect Dis Res Africa, Inst Infect Dis & Mol Med, Cape Town, South Africa.;Univ Cape Town, Dept Med, Cape Town, South Africa..
    Meintjes, Graeme
    Univ Cape Town, Wellcome Ctr Infect Dis Res Africa, Inst Infect Dis & Mol Med, Cape Town, South Africa.;Univ Cape Town, Dept Med, Cape Town, South Africa..
    Joubert, Anton
    Univ Cape Town, Dept Med, Div Clin Pharmacol, Cape Town, South Africa..
    Norman, Jennifer
    Univ Cape Town, Dept Med, Div Clin Pharmacol, Cape Town, South Africa..
    Castel, Sandra
    Univ Cape Town, Dept Med, Div Clin Pharmacol, Cape Town, South Africa..
    Gandhi, Neel R.
    Emory Univ, Rollins Sch Publ Hlth, Atlanta, GA 30322 USA.;Emory Univ, Emory Sch Med, Atlanta, GA 30322 USA..
    Denti, Paolo
    Univ Cape Town, Dept Med, Div Clin Pharmacol, Cape Town, South Africa..
    McIlleron, Helen
    Univ Cape Town, Dept Med, Div Clin Pharmacol, Cape Town, South Africa.;Univ Cape Town, Wellcome Ctr Infect Dis Res Africa, Inst Infect Dis & Mol Med, Cape Town, South Africa.;Univ Cape Town, Dept Med, Cape Town, South Africa..
    Svensson, Elin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Radboud Univ Nijmegen, Med Ctr, Radboud Inst Hlth Sci, Dept Pharm, Nijmegen, Netherlands..
    Wiesner, Lubbe
    Univ Cape Town, Dept Med, Div Clin Pharmacol, Cape Town, South Africa..
    Relationship between Plasma and Intracellular Concentrations of Bedaquiline and Its M2 Metabolite in South African Patients with Rifampin-Resistant Tuberculosis2021In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 65, no 11, article id e02399-20Article in journal (Refereed)
    Abstract [en]

    Bedaquiline is recommended for the treatment of all patients with rifampin-resistant tuberculosis (RR-TB). Bedaquiline accumulates within cells, but its intracellular pharmacokinetics have not been characterized, which may have implications for dose optimization. We developed a novel assay using high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) to measure the intracellular concentrations of bedaquiline and its primary metabolite M2 in patients with RR-TB in South Africa. Twenty-one participants were enrolled and underwent sparse sampling of plasma and peripheral blood mononuclear cells (PBMCs) at months 1, 2, and 6 of treatment and at 3 and 6 months after bedaquiline treatment completion. Intensive sampling was performed at month 2. We used noncompartmental analysis to describe plasma and intracellular exposures and a population pharmacokinetic model to explore the relationship between plasma and intracellular pharmacokinetics and the effects of key covariates. Bedaquiline concentrations from month 1 to month 6 of treatment ranged from 94.7 to 2,540 ng/ml in plasma and 16.2 to 5,478 ng/ml in PBMCs, and concentrations of M2 over the 6-month treatment period ranged from 34.3 to 496 ng/ml in plasma and 109.2 to 16,764 ng/ml in PBMCs. Plasma concentrations of bedaquiline were higher than those of M2, but intracellular concentrations of M2 were considerably higher than those of bedaquiline. In the pharmacokinetic modeling, we estimated a linear increase in the intracellular-plasma accumulation ratio for bedaquiline and M2, reaching maximum effect after 2 months of treatment. The typical intracellular-plasma ratios 1 and 2 months after start of treatment were 0.61 (95% confidence interval [CI]: 0.42 to 0.92) and 1.10 (95% CI: 0.74 to 1.63) for bedaquiline and 12.4 (95% CI: 8.8 to 17.8) and 22.2 (95% CI: 15.6 to 32.3) for M2. The intracellular-plasma ratios for both bedaquiline and M2 were decreased by 54% (95% CI: 24 to 72%) in HIV-positive patients compared to HIV-negative patients. Bedaquiline and M2 were detectable in PBMCs 6 months after treatment discontinuation. M2 accumulated at higher concentrations intracellularly than bedaquiline, supporting in vitro evidence that M2 is the main inducer of phospholipidosis.

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  • 35.
    Pieterman, E. D.
    et al.
    Erasmus MC, Dept Med Microbiol & Infect Dis, Rotterdam, Netherlands..
    van den Berg, S.
    Erasmus MC, Dept Med Microbiol & Infect Dis, Rotterdam, Netherlands..
    van der Meijden, A.
    Erasmus MC, Dept Med Microbiol & Infect Dis, Rotterdam, Netherlands..
    Svensson, Elin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Radboud Univ Nijmegen, Radboud Inst Hlth Sci, Dept Pharm, Med Ctr, Nijmegen, Netherlands..
    Bax, H. , I
    de Steenwinkel, J. E. M.
    Erasmus MC, Dept Med Microbiol & Infect Dis, Rotterdam, Netherlands..
    Higher Dosing of Rifamycins Does Not Increase Activity against Mycobacterium tuberculosis in the Hollow-Fiber Infection Model2021In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 65, no 4, article id e02255-20Article in journal (Refereed)
    Abstract [en]

    Improvements in the translational value of preclinical models can allow more-successful and more-focused research on shortening the duration of tuberculosis treatment. Although the hollow-fiber infection model (HFIM) is considered a valuable addition to the drug development pipeline, its exact role has not been fully determined yet. Since the strategy of increasing the dose of rifamycins is being evaluated for its treatment-shortening potential, additional in vitro modeling is important. Therefore, we assessed increased dosing of rifampin and rifapentine in our HFIM in order to gain more insight into the place of the HFIM in the drug development pipeline. Total and free-fraction concentrations corresponding to daily dosing of 2.7, 10, and 50 mg of rifampin/kg of body weight, as well as 600 mg and 1,500 mg rifapentine, were assessed in our HFIM using the Mycobacterium tuberculosis H37Rv strain. Drug activity and the emergence of drug resistance were assessed by CFU counting and subsequent mathematical modeling over 14 days, and pharmacokinetic exposures were checked. We found that increasing rifampin exposure above what is expected with the standard dose did not result in higher antimycobacterial activity. For rifapentine, only the highest concentration showed increased activity, but the clinical relevance of this observation is questionable. Moreover, for both drugs, the emergence of resistance was unrelated to exposure. In conclusion, in the simplest experimental setup, the results of the HFIM did not fully correspond to preexisting clinical data. The inclusion of additional parameters and readouts in this preclinical model could be of interest for proper assessment of the translational value of the HFIM.

  • 36.
    Prins, H. A. B.
    et al.
    Erasmus MC, Dept Med Microbiol & Infect Dis, Rotterdam, Netherlands.;Dept Internal Med, Rotterdam, Netherlands..
    Zino, L.
    Radboud Univ Nijmegen, Dept Pharm, Med Ctr, POB 9101, 9101, Geert Grootepl Zuid 10,route 864, NL-6500 HB Nijmegen, Netherlands.;Radboud Inst Hlth Sci, POB 9101, 9101, Geert Grootepl Zuid 10,route 864, NL-6500 HB Nijmegen, Netherlands..
    Svensson, Elin M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Radboud Univ Nijmegen, Dept Pharm, Med Ctr, POB 9101, 9101, Geert Grootepl Zuid 10,route 864, NL-6500 HB Nijmegen, Netherlands.;Radboud Inst Hlth Sci, POB 9101, 9101, Geert Grootepl Zuid 10,route 864, NL-6500 HB Nijmegen, Netherlands.
    Verbon, A.
    Erasmus MC, Dept Med Microbiol & Infect Dis, Rotterdam, Netherlands.;Dept Internal Med, Rotterdam, Netherlands..
    de Bree, G. J.
    Univ Amsterdam, Amsterdam Univ, Dept Internal Med, Div Infect Dis,Med Ctr, Amsterdam, Netherlands.;Amsterdam Inst Infect & Immun, Amsterdam, Netherlands..
    Prins, J. M.
    Univ Amsterdam, Amsterdam Univ, Dept Internal Med, Div Infect Dis,Med Ctr, Amsterdam, Netherlands.;Amsterdam Inst Infect & Immun, Amsterdam, Netherlands..
    Reiss, P.
    Univ Amsterdam, Amsterdam Univ, Dept Internal Med, Div Infect Dis,Med Ctr, Amsterdam, Netherlands.;Amsterdam Inst Infect & Immun, Amsterdam, Netherlands.;Univ Amsterdam, Amsterdam Univ, Dept Global Hlth, Med Ctr, Amsterdam, Netherlands.;Amsterdam Inst Global Hlth & Dev, Amsterdam, Netherlands..
    Burger, D. M.
    Radboud Univ Nijmegen, Dept Pharm, Med Ctr, POB 9101, 9101, Geert Grootepl Zuid 10,route 864, NL-6500 HB Nijmegen, Netherlands.;Radboud Inst Hlth Sci, POB 9101, 9101, Geert Grootepl Zuid 10,route 864, NL-6500 HB Nijmegen, Netherlands..
    Rokx, C.
    Erasmus MC, Dept Med Microbiol & Infect Dis, Rotterdam, Netherlands.;Dept Internal Med, Rotterdam, Netherlands..
    Colbers, A.
    Radboud Univ Nijmegen, Dept Pharm, Med Ctr, POB 9101, 9101, Geert Grootepl Zuid 10,route 864, NL-6500 HB Nijmegen, Netherlands.;Radboud Inst Hlth Sci, POB 9101, 9101, Geert Grootepl Zuid 10,route 864, NL-6500 HB Nijmegen, Netherlands..
    Team, NOVA Study
    Exposure and virologic outcomes of dolutegravir combined with ritonavir boosted darunavir in treatment-naive individuals enrolled in the Netherlands Cohort Study on Acute HIV infection (NOVA)2023In: International Journal of Antimicrobial Agents, ISSN 0924-8579, E-ISSN 1872-7913, Vol. 61, no 1, article id 106697Article in journal (Refereed)
    Abstract [en]

    To the authors' knowledge, there is currently no literature or guidance recommendation regard-ing whether the dose of dolutegravir (DTG) should be increased when co-administered with darunavir/ritonavir (DRV/r) in patients with acute human immunodeficiency virus infection (AHI). This study assessed the pharmacokinetics (PK) of twice-daily (BID) DTG and once-daily (QD) DRV/r, and com-pared this with DTG QD without DRV/r in patients with AHI. Forty-six participants initiated antiretro-viral therapy within < 24 h of enrolment: DTG 50 mg BID, DRV/r 80 0/10 0 mg QD, and two nucleoside reverse transcriptase inhibitors (NRTIs) for 4 weeks (Phase I); and DTG 50 mg QD with two NRTIs there-after (Phase II: reference). Total DTG trough concentration (Ctrough) and area under the concentration-time profile of 0-24 h (AUC0-24h) were predicted using a population PK model. DTG glucuronidation metabolic ratio (MR) and DTG free fraction were determined and compared per treatment phase using geometric mean ratio (GMR) and 90% confidence interval (CI). Participants had a predicted geometric mean steady-state DTG Ctrough of 2.83 [coefficient of variation (CV%) 30.3%] mg/L (Phase I) and 1.28 (CV% 52.4%) mg/L (Phase II), with GMR of 2.20 (90% CI 1.90-2.55). Total exposure during DTG BID increased but did not double [AUC0-24h GMR 1.65 (90% CI 1.50-1.81) h.mg/L]. DTG glucuronidation MR increased by approxi-mately 29% during Phase I. DTG Ctrough was above in-vivo EC90 (0.32 mg/L) during both phases, except in one participant during Phase I. At Week 8, 84% of participants had viral loads <= 40 copies/mL. The drug-drug interaction between DTG (BID) and DRV/r (QD) was due to induced glucuronidation, and is not clinically relevant in patients with AHI.(c) 2022 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license ( http://creativecommons.org/licenses/by/4.0/ )

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  • 37.
    Radtke, Kendra K.
    et al.
    Univ Calif San Francisco, Bioengn & Therapeut Sci, San Francisco, CA 94143 USA..
    Svensson, Elin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Radboud Univ Nijmegen, Med Ctr, Dept Pharm, Nijmegen, Netherlands..
    van der Laan, Louvina E.
    Stellenbosch Univ, Dept Paediat & Child Hlth, Desmond Tutu TB Ctr, Tygerberg, South Africa..
    Hesseling, Anneke C.
    Stellenbosch Univ, Dept Paediat & Child Hlth, Desmond Tutu TB Ctr, Tygerberg, South Africa..
    Savic, Radojka M.
    Univ Calif San Francisco, Bioengn & Therapeut Sci, San Francisco, CA 94143 USA..
    Garcia-Prats, Anthony J.
    Stellenbosch Univ, Dept Paediat & Child Hlth, Desmond Tutu TB Ctr, Tygerberg, South Africa.;Univ Wisconsin, Dept Pediat, Madison, WI USA..
    Emerging data on rifampicin pharmacokinetics and approaches to optimal dosing in children with tuberculosis2022In: Expert Review of Clinical Pharmacology, ISSN 1751-2433, E-ISSN 1751-2441, Vol. 15, no 2, p. 161-174Article, review/survey (Refereed)
    Abstract [en]

    Introduction Despite its longstanding role in tuberculosis (TB) treatment, there continues to be emerging rifampicin research that has important implications for pediatric TB treatment and outstanding questions about its pharmacokinetics and optimal dose in children. Areas covered This review aims to summarize and discuss emerging data on the use of rifampicin for: 1) routine treatment of drug-susceptible TB; 2) special subpopulations such as children with malnutrition, HIV, or TB meningitis; 3) treatment shortening. We also highlight the implications of these new data for child-friendly rifampicin formulations and identify future research priorities. Expert opinion New data consistently show low rifampicin exposures across all pediatric populations with 10-20 mg/kg dosing. Although clinical outcomes in children are generally good, rifampicin dose optimization is needed, especially given a continued push to shorten treatment durations and for specific high-risk populations of children who have worse outcomes. A pooled analysis of existing data using applied pharmacometrics would answer many of the important questions remaining about rifampicin pharmacokinetics needed to optimize doses, especially in special populations. Targeted clinical studies in children with TB meningitis and treatment shortening with high-dose rifampicin are also priorities.

  • 38.
    Ruth, Mike Marvin
    et al.
    Radboud Univ Nijmegen, Radboudumc Ctr Infect Dis, Dept Med Microbiol, Med Ctr, Nijmegen, Netherlands.
    Koeken, Valerie A. C. M.
    Radboud Univ Nijmegen, Radboudumc Ctr Infect Dis, Dept Internal Med, Med Ctr, Nijmegen, Netherlands.
    Pennings, Lian J.
    Radboud Univ Nijmegen, Radboudumc Ctr Infect Dis, Dept Med Microbiol, Med Ctr, Nijmegen, Netherlands.
    Svensson, Elin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Radboud Univ Nijmegen, Radboudumc Ctr Infect Dis, Dept Pharm, Med Ctr, Nijmegen, Netherlands.
    Wertheim, Heiman F. L.
    Radboud Univ Nijmegen, Radboudumc Ctr Infect Dis, Dept Med Microbiol, Med Ctr, Nijmegen, Netherlands.
    Hoefsloot, Wouter
    Radboud Univ Nijmegen, Radboudumc Ctr Infect Dis, Dept Pulm Dis, Med Ctr, Nijmegen, Netherlands.
    van Ingen, Jakko
    Radboud Univ Nijmegen, Radboudumc Ctr Infect Dis, Dept Med Microbiol, Med Ctr, Nijmegen, Netherlands.
    Is there a role for tedizolid in the treatment of non-tuberculous mycobacterial disease?2020In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 75, no 3, p. 609-617Article in journal (Refereed)
    Abstract [en]

    Background: Pulmonary infections caused by non-tuberculous mycobacteria (NTM) are hard to treat and have low cure rates despite intensive multidrug therapy.

    Objectives: To assess the feasibility of tedizolid, a new oxazolidinone, for the treatment of Mycobacterium avium and Mycobacterium abscessus.

    Methods: We determined MICs of tedizolid for 113 isolates of NTM. Synergy with key antimycobacterial drugs was assessed using the chequerboard method and calculation of the FIC index (FICI). We performed time-kill kinetics assays of tedizolid alone and combined with amikacin for M. abscessus and with ethambutol for M. avium. Human macrophages were infected with M. abscessus and M. avium and subsequently treated with tedizolid; intracellular and extracellular cfu were quantified over time.

    Results: NTM isolates generally had a lower MIC of tedizolid than of linezolid. FICIs were lowest between tedizolid and amikacin for M. abscessus (FICI = 0.75) and between tedizolid and ethambutol for M. avium (FICI = 0.72). Clarithromycin and tedizolid showed initial synergy, which was abrogated by erm(41)-induced macrolide resistance (FICI = 0.53). Tedizolid had a weak bacteriostatic effect on M. abscessus and combination with amikacin slightly prolonged its effect. Tedizolid had concentration-dependent activity against M. avium and its efficacy was enhanced by ethambutol. Both combinations had a concentration-dependent synergistic effect. Tedizolid could inhibit the intracellular bacterial population of both M. avium and M. abscessus.

    Conclusions: Tedizolid should be further investigated in pharmacodynamic studies and clinical trials for M. avium complex pulmonary disease. It is less active against M. abscessus, but still promising.

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  • 39.
    Ruth, Mike Marvin
    et al.
    Radboud Univ Nijmegen, Radboudumc Ctr Infect Dis, Dept Med Microbiol, Med Ctr, Nijmegen, Netherlands..
    Raaijmakers, Jelmer
    Radboud Univ Nijmegen, Radboudumc Ctr Infect Dis, Dept Med Microbiol, Med Ctr, Nijmegen, Netherlands..
    van den Hombergh, Erik
    Radboud Univ Nijmegen, Dept Pharm, Med Ctr, Nijmegen, Netherlands..
    Aarnoutse, Rob
    Radboud Univ Nijmegen, Dept Pharm, Med Ctr, Nijmegen, Netherlands..
    Svensson, Elin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Radboud Univ Nijmegen, Radboudumc Ctr Infect Dis, Dept Pharm, Med Ctr, Nijmegen, Netherlands..
    Susanto, Budi Octasari
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Simonsson, Ulrika S. H.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Wertheim, Heiman
    Radboud Univ Nijmegen, Radboudumc Ctr Infect Dis, Dept Med Microbiol, Med Ctr, Nijmegen, Netherlands..
    Hoefsloot, Wouter
    Radboud Univ Nijmegen, Radboudumc Ctr Infect Dis, Dept Pulm Dis, Med Ctr, Nijmegen, Netherlands..
    van Ingen, Jakko
    Radboud Univ Nijmegen, Radboudumc Ctr Infect Dis, Dept Med Microbiol, Med Ctr, Nijmegen, Netherlands..
    Standard therapy of Mycobacterium avium complex pulmonary disease shows limited efficacy in an open source hollow fibre system that simulates human plasma and epithelial lining fluid pharmacokinetics2022In: Clinical Microbiology and Infection, ISSN 1198-743X, E-ISSN 1469-0691, Vol. 28, no 3, p. 448.e1-448.e7Article in journal (Refereed)
    Abstract [en]

    Objectives: Mycobacterium avium complex (MAC) bacteria can cause chronic pulmonary disease (PD). Current treatment regimens of azithromycin, ethambutol and rifampicin have culture conversion rates of around 65%. Dynamic, preclinical models to assess the efficacy of treatment regimens are important to guide clinical trial development. The hollow fibre system (HFS) has been applied but reports lack experimental details.

    Methods: We simulated the human pharmacokinetics of azithromycin, ethambutol and rifampicin both in plasma and epithelial lining fluid (ELF) in a HFS, exposing THP-1 cells infected with M. avium to the triple-drug regimen for 3 weeks. We accounted for drug-drug interactions and protein-binding and provide all laboratory protocols. We differentiated the effects on the intracellular and extracellular mycobacterial population.

    Results: The antibiotic concentrations in the HFS accurately reflected the time to peak concentration (T-max), the peak concentration (C-max) and half-life of azithromycin, rifampicin and ethambutol in plasma and ELF reported in literature. We find that plasma drug concentrations fail to hold the MAC bacterial load static (Delta Log10 CFU/ml(Control:Regimen) = 0.66 +/- 0.76 and 0.45 +/- 0.28 at 3 and 21 days); ELF concentrations do hold the bacterial load static for 3 days and inhibit bacterial growth for the duration of the experiment (Delta Log10 CFU/ml(Control:Regimen) = 1.1 +/- 0.1 and 1.64 +/- 0.59 at 3 and 21 days).

    Discussion: In our model, the current therapy against MAC is ineffective, even when accounting for antibiotic accumulation at the site of infection and intracellularly. New treatment regimens need to be developed and be compared with currently recommended regimens in dynamic models prior to clinical evaluation. With the publication of all protocols we aim to open this technology to new users.

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  • 40.
    Ruth, Mike Marvin
    et al.
    Radboud Univ Nijmegen, Dept Med Microbiol, Med Ctr, Nijmegen, Netherlands.
    Sangen, Jasper J. N.
    Radboud Univ Nijmegen, Dept Med Microbiol, Med Ctr, Nijmegen, Netherlands.
    Remmers, Karlijn
    Radboud Univ Nijmegen, Dept Med Microbiol, Med Ctr, Nijmegen, Netherlands.
    Pennings, Lian J.
    Radboud Univ Nijmegen, Dept Med Microbiol, Med Ctr, Nijmegen, Netherlands.
    Svensson, Elin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Radboud Univ Nijmegen, Dept Pharm, Med Ctr, Nijmegen, Netherlands.
    Aarnoutse, Rob E.
    Radboud Univ Nijmegen, Dept Pharm, Med Ctr, Nijmegen, Netherlands.
    Zweijpfenning, Sanne M. H.
    Radboud Univ Nijmegen, Dept Pulm Dis, Med Ctr, Nijmegen, Netherlands.
    Hoefsloot, Wouter
    Radboud Univ Nijmegen, Dept Pulm Dis, Med Ctr, Nijmegen, Netherlands.
    Kuipers, Saskia
    Radboud Univ Nijmegen, Dept Med Microbiol, Med Ctr, Nijmegen, Netherlands.
    Magis-Escurra, Cecile
    Radboud Univ Nijmegen, Dept Pulm Dis, Med Ctr, Nijmegen, Netherlands.
    Wertheim, Heiman F. L.
    Radboud Univ Nijmegen, Dept Med Microbiol, Med Ctr, Nijmegen, Netherlands.
    van Ingen, Jakko
    Radboud Univ Nijmegen, Dept Med Microbiol, Med Ctr, Nijmegen, Netherlands.
    A bedaquiline/clofazimine combination regimen might add activity to the treatment of clinically relevant non-tuberculous mycobacteria2019In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 74, no 4, p. 935-943Article in journal (Refereed)
    Abstract [en]

    Background: Non-tuberculous mycobacteria (NTM) infections are hard to treat. New antimicrobial drugs and smarter combination regimens are needed.

    Objectives: Our aim was to determine the in vitro activity of bedaquiline against NTM and assess its synergy with established antimycobacterials.

    Methods: We determined MICs of bedaquiline for clinically relevant NTM species and Mycobacterium tuberculosis by broth microdilution for 30 isolates. Synergy testing was performed using the chequerboard method for 22 reference strains and clinical isolates of Mycobacterium abscessus (MAB) and Mycobacterium avium complex (MAC). Time-kill kinetics (TK) assays with resistance monitoring of bedaquiline alone and combined with clofazimine were performed for MAB CIP 104536 and M. avium ATCC 700898; bedaquiline/clarithromycin combinations were evaluated against M. avium ATCC 700898. Interactions were assessed for TK experiments based on Bliss independence.

    Results: Bedaquiline had modest activity against tested NTM, with MICs between <0.007and 1mg/L. Bedaquiline showed no interaction with tested drugs against MAB or MAC. Lowest mean fractional inhibitory concentration index (FICI) values were 0.79 with clofazimine for MAB and 0.97 with clofazimine and 0.82 with clarithromycin for MAC. In TK assays, bedaquiline showed a bacteriostatic effect. Clofazimine extended the bacteriostatic activity of bedaquiline against MAB and yielded a slight bactericidal effect against M. avium. The bedaquiline/clofazimine combination slowed emergence of bedaquiline resistance for M. avium but promoted it for MAB. Relative to Bliss independence, bedaquiline/clofazimine showed synergistic interaction over time for MAB and no interaction for M. avium and bedaquiline/clarithromycin showed antagonistic interaction for M. avium.

    Conclusions: Following these in vitro data, a bedaquiline/clofazimine combination might add activity to MAB and MAC treatment. The bedaquiline/clarithromycin combination might have lower activity compared with bedaquiline alone for MAC treatment.

  • 41.
    Ruth, Mike Marvin
    et al.
    Radboud Univ Nijmegen, Med Ctr, Dept Med Microbiol, Radboud Ctr Infect Dis, Nijmegen, Netherlands.
    van Rossum, Mara
    Radboud Univ Nijmegen, Med Ctr, Dept Med Microbiol, Radboud Ctr Infect Dis, Nijmegen, Netherlands.
    Koeken, Valerie A. C. M.
    Radboud Univ Nijmegen, Med Ctr, Dept Internal Med, Radboud Ctr Infect Dis, Nijmegen, Netherlands.
    Pennings, Lian J.
    Radboud Univ Nijmegen, Med Ctr, Dept Med Microbiol, Radboud Ctr Infect Dis, Nijmegen, Netherlands.
    Svensson, Elin M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Radboud Univ Nijmegen, Med Ctr, Dept Pharm, Radboud Ctr Infect Dis, Nijmegen, Netherlands.
    Ruesen, Carolien
    Radboud Univ Nijmegen, Med Ctr, Dept Med Microbiol, Radboud Ctr Infect Dis, Nijmegen, Netherlands.
    Bowles, Edmee C.
    Radboud Univ Nijmegen, Med Ctr, Dept Med Microbiol, Radboud Ctr Infect Dis, Nijmegen, Netherlands.
    Wertheim, Heiman F. L.
    Radboud Univ Nijmegen, Med Ctr, Dept Med Microbiol, Radboud Ctr Infect Dis, Nijmegen, Netherlands.
    Hoefsloot, Wouter
    Radboud Univ Nijmegen, Med Ctr, Dept Pulm Dis, Radboud Ctr Infect Dis, Nijmegen, Netherlands.
    van Ingen, Jakko
    Radboud Univ Nijmegen, Med Ctr, Dept Med Microbiol, Radboud Ctr Infect Dis, Nijmegen, Netherlands.
    Auranofin Activity Exposes Thioredoxin Reductase as a Viable Drug Target in Mycobacterium abscessus2019In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 63, no 9, article id e00449-19Article in journal (Refereed)
    Abstract [en]

    Nontuberculous mycobacteria (NTM) are highly drug-resistant, opportunistic pathogens that can cause pulmonary disease. The outcomes of the currently recommended treatment regimens are poor, especially for Mycobacterium abscessus. New or repurposed drugs are direly needed. Auranofin, a gold-based antirheumatic agent, was investigated for Mycobacterium tuberculosis. Here, we test auranofin against NTM in vitro and ex vivo. We tested the susceptibility of 63 NTM isolates to auranofin using broth microdilution. Next, we assessed synergy between auranofin and antimycobacterial drugs using the checkerboard method and calculated the fractional inhibition concentration index (FICI). Using time-kill kinetics assays (TK), we assessed pharmacodynamics of auranofin alone and in combination with drug combinations showing the lowest FICIs for M. abscessus CIP 104536. A response surface analysis was used to assess synergistic interactions over time in TKs. Primary isolated macrophages were infected with M. abscessus and treated with auranofin. Finally, using KEGG Orthology, we looked for orthologues to auranofins drug target in M. tuberculosis. M. abscessus had the lowest auranofin MIC50 (2 mu g/ml) among the tested NTM. The lowest average FICIs were observed between auranofin and amikacin (0.45) and linezolid (0.50). Auranofin exhibited concentration-dependent killing of M. abscessus, with >1-log killing at concentrations of >2x MIC. Only amikacin was synergistic with auranofin according to Bliss independence. Auranofin could not lower the intracellular bacterial load in macrophages. Auranofin itself may not be feasible for M. abscessus treatment, but these data point toward a promising, unutilized drug target.

  • 42.
    Ryeznik, Yevgen
    et al.
    AstraZeneca, R&D Biopharmaceut, Data Sci & AI, BioPharma Early Biometr & Stat Innovat, Gothenburg, Sweden..
    Sverdlov, Oleksandr
    Novartis Pharmaceut, Early Dev Analyt, E Hanover, NJ USA..
    Svensson, Elin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Radboud Univ Nijmegen, Med Ctr, Radboud Inst Hlth Sci, Dept Pharm, Nijmegen, Netherlands..
    Montepiedra, Grace
    Harvard TH Chan Sch Publ Hlth, Ctr Biostat AIDS Res, Boston, MA USA..
    Hooker, Andrew
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Wong, Weng Kee
    Univ Calif Los Angeles, Dept Biostat, Los Angeles, CA USA..
    Pharmacometrics meets statistics-A synergy for modern drug development2021In: CPT: Pharmacometrics and Systems Pharmacology (PSP), E-ISSN 2163-8306, Vol. 10, no 10, p. 1134-1149Article in journal (Refereed)
    Abstract [en]

    Modern drug development problems are very complex and require integration of various scientific fields. Traditionally, statistical methods have been the primary tool for design and analysis of clinical trials. Increasingly, pharmacometric approaches using physiology-based drug and disease models are applied in this context. In this paper, we show that statistics and pharmacometrics have more in common than what keeps them apart, and collectively, the synergy from these two quantitative disciplines can provide greater advances in clinical research and development, resulting in novel and more effective medicines to patients with medical need.

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  • 43.
    Sasaki, Tomohiro
    et al.
    Otsuka Pharmaceut Co Ltd, Osaka, Japan..
    Svensson, Elin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Radboud Univ Nijmegen, Dept Pharm, Med Ctr, Nijmegen, Netherlands..
    Wang, Xiaofeng
    Otsuka Pharmaceut Dev & Commercializat Inc, Rockville, MD USA..
    Wang, Yanlin
    Otsuka Pharmaceut Dev & Commercializat Inc, Rockville, MD USA..
    Hafkin, Jeffrey
    Otsuka Pharmaceut Dev & Commercializat Inc, Rockville, MD USA..
    Karlsson, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Mallikaarjun, Suresh
    Otsuka Pharmaceut Dev & Commercializat Inc, Rockville, MD USA..
    Population Pharmacokinetic and Concentration-QTc Analysis of Delamanid in Pediatric Participants with Multidrug-Resistant Tuberculosis2022In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 66, no 2, article id e01608-21Article in journal (Refereed)
    Abstract [en]

    A population pharmacokinetic analysis of delamanid and its major metabolite DM-6705 was conducted to characterize the pharmacokinetics of delamanid and DM-6705 in pediatric participants with multidrug-resistant tuberculosis (MDR-TB). Data from participants between the ages of 0.67 and 17 years, enrolled in 2 clinical trials, were utilized for the analysis. The final data set contained 634 delamanid and 706 DM-6705 valid plasma concentrations from 37 children. A transit model with three compartments best described the absorption of delamanid. Two-compartment models for each component with linear elimination were selected to characterize the dispositions of delamanid and DM-6705, respectively. The covariates included in the model were body weight on the apparent volume of distribution and apparent clearance (for both delamanid and DM-6705); formulation (dispersible versus film-coated tablet) on the mean absorption time; age, formulation, and dose on the bioavailability of delamanid; and age on the fraction of delamanid metabolized to DM-6705. Based on the simulations, doses for participants within different age/weight groups that result in delamanid exposure comparable to that in adults following the approved adult dose were calculated. By concentration-QTc (QTcB [QT corrected by Bazett's formula]) analysis, a significant positive correlation was detected with concentrations of DM-6705. However, the modelpredicted upper bounds of the 90% confidence intervals of Delta QTc values were <10 ms at the simulated maximum concentration (C-max) of DM-6705 following the administration of the maximum doses simulated. This suggests that the effect on the QT interval following the proposed dosing is unlikely to be clinically meaningful in children with MDRTB who receive delamanid.

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  • 44.
    Singh, K. P.
    et al.
    Univ Melbourne, Peter Doherty Inst Infect & Immun, Dept Infect Dis, Melbourne, Vic, Australia.;Royal Melbourne Hosp, Victorian Infect Dis Unit, Melbourne, Vic, Australia..
    Carvalho, A. C. C.
    Fundacao Oswaldo Cruz, Lab Inovacoes Terapias Ensino & Bioprod LITEB, Inst Oswaldo Cruz, Rio De Janeiro, RJ, Brazil..
    Centis, R.
    Ist Ricovero & Cura Carattere Sci IRCCS, Serv Epidemiol Clin Malattie Resp, Ist Clin Sci Maugeri, Tradate, Italy..
    D'Ambrosio, L.
    Publ Hlth Consulting Grp, Lugano, Switzerland..
    Migliori, G. B.
    Ist Ricovero & Cura Carattere Sci IRCCS, Serv Epidemiol Clin Malattie Resp, Ist Clin Sci Maugeri, Tradate, Italy..
    Mpagama, S. G.
    Kilimanjaro Christian Med Univ Coll, Moshi, Tanzania.;Kibongoto Infect Dis Hosp, Siha, Kilimanjaro, Tanzania..
    Nguyen, B. C.
    Woolcock Inst Med Res, Hanoi, Vietnam..
    Aarnoutse, R. E.
    Radboud Univ Nijmegen, Res Inst Med Innovat, Dept Pharm, Med Ctr, Nijmegen, Netherlands..
    Aleksa, A.
    Grodno State Med Univ, Grodno, BELARUS..
    van Altena, R.
    Asian Harm Reduct Network AHRN, Yangon, Myanmar.;Med Act MAM, Yangon, Myanmar..
    Bhavani, P. K.
    Indian Council Med Res, Natl Inst Res TB, Chennai, India..
    Bolhuis, M. S.
    Univ Groningen, Univ Med Ctr Groningen, Dept Clin Pharm & Pharmacol, Groningen, Netherlands..
    Borisov, S.
    Moscow Res & Clin Ctr TB Control, Moscow, Russia..
    van't Boveneind-Vrubleuskaya, N.
    Univ Groningen, Univ Med Ctr Groningen, Dept Clin Pharm & Pharmacol, Groningen, Netherlands.;Metropolitan Publ Hlth Serv, Dept Publ Hlth TB Control, The Hague, Netherlands..
    Bruchfeld, J.
    Karolinska Inst, Dept Med Solna, Div Infect Dis, Stokholm, Sweden.;Karolinska Univ Hosp, Dept Infect Dis, Stockholm, Sweden..
    Caminero, J. A.
    Univ Gen Hosp Gran Canaria Dr Negrin, Dept Pneumol, Las Palmas Gran Canaria, Spain.;ALOSA Act Learning Sanitary Aspects TB Acad, Madrid, Spain..
    Carvalho, I.
    Vila Nova de Gaia Hosp Ctr, Vila Nova de Gaia Outpatient TB Ctr, Paediat Dept, Vila Nova De Gaia, Portugal..
    Cho, J. G.
    Univ Sydney, Sydney Infecious Dis Inst Sydney ID, Sydney, NSW, Australia.;Westmead Hosp, Sydney, NSW, Australia.;Parramatta Chest Clin, Parramatta, NSW, Australia..
    Forsman, L. Davies
    Karolinska Inst, Dept Med Solna, Div Infect Dis, Stokholm, Sweden.;Karolinska Univ Hosp, Dept Infect Dis, Stockholm, Sweden.;Univ Sydney, Fac Med & Hlth, Sch Pharm, Sydney, NSW, Australia..
    Dedicoat, M.
    Univ Hosp Birmingham NHS Fdn Trust, Heartlands Hosp, Dept Infect Dis, Birmingham, England..
    Dheda, K.
    Univ Cape Town, Ctr Lung Infect, Cape Town, South Africa.;Univ Cape Town, Dept Med, Div Pulmonol, Immun Unit, Cape Town, South Africa.;Univ Cape Town, UCT Lung Inst, Cape Town, South Africa.;Univ Cape Town, South African Med Res Council, Ctr Study Antimicrobial Resistance, Cape Town, South Africa.;London Sch Hyg & Trop Med, Fac Infect & Trop Dis, London, England..
    Dooley, K.
    Vanderbilt Univ, Dept Med, Div Infect Dis, Med Ctr, Nashville, TN USA..
    Furin, J.
    Harvard Med Sch, Dept Global Hlth & Social Med, Boston, MA USA..
    Garcia-Garcia, J. M.
    SEPAR Soc Espanola Neumol & Cirugia Torac, TB Res Programme, Barcelona, Spain..
    Garcia-Prats, A.
    Stellenbosch Univ, Desmond Tutu TB Ctr, Dept Paediat & Child Hlth, Tygerberg, South Africa.;Univ Wisconsin, Dept Pediat, Madison, WI USA..
    Hesseling, A. C.
    Stellenbosch Univ, Desmond Tutu TB Ctr, Dept Paediat & Child Hlth, Tygerberg, South Africa..
    Heysell, S. K.
    Univ Virginia, Div Infect Dis & Int Hlth, Charlottesville, VA USA..
    Hu, Y.
    Fudan Univ, Sch Publ Hlth, Dept Epidemiol, Shanghai, Peoples R China.;Fudan Univ, Key Lab Publ Hlth Safety, Shanghai, Peoples R China..
    Kim, H. Y.
    Univ Sydney, Sydney Infecious Dis Inst Sydney ID, Sydney, NSW, Australia.;Westmead Hosp, Sydney, NSW, Australia.;Univ Sydney, Fac Med & Hlth, Sch Pharm, Sydney, NSW, Australia..
    Manga, S.
    Latin Amer Soc Thorac Dis, TB Dept, Lima, Peru..
    Marais, B. J.
    Univ Cape Town, South African Med Res Council, Ctr Study Antimicrobial Resistance, Cape Town, South Africa.;Childrens Hosp Westmead, Dept Infect Dis & Microbiol, Westmead, NSW, Australia..
    Margineanu, I.
    Univ Groningen, Univ Med Ctr Groningen, Dept Clin Pharm & Pharmacol, Groningen, Netherlands..
    Martson, A-G
    Torrico, M. Munoz
    Inst Nacl Enfermedades Respiratorias, Clin TB, Mexico City, Mexico..
    Nataprawira, H. M.
    Univ Padjadjaran, Hasan Sadikin Hosp, Fac Med, Dept Child Hlth,Div Paediat Respirol, Bandung, Indonesia..
    Nunes, E.
    Cent Hosp Maputo, Dept Pulmonol, Maputo, Mozambique.;Eduardo Mondlane Univ, Fac Med, Maputo, Mozambique..
    Ong, C. W. M.
    Ist Ricovero & Cura Carattere Sci IRCCS, Serv Epidemiol Clin Malattie Resp, Ist Clin Sci Maugeri, Tradate, Italy.;Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Med, Infect Dis Translat Res Programme, Singapore, Singapore.;Natl Univ Singapore, Inst Hlth Innovat & Technol iHealthtech, Singapore, Singapore.;Natl Univ Singapore Hosp, Dept Med, Div Infect Dis, Singapore, Singapore..
    Otto-Knapp, R.
    German Cent Comm TB DZK, Berlin, Germany..
    Palmero, D. J.
    Hosp Muniz, Buenos Aires, Argentina.;Inst Vaccarezza, Buenos Aires, Argentina..
    Peloquin, C. A.
    Univ Florida, Coll Pharm, Infect Dis Pharmacokinet Lab, Gainesville, FL USA.;Univ Florida, Emerging Pathogens Inst, Gainesville, FL USA..
    Rendon, A.
    Univ Autonoma Nuevo Leon, Fac Med, Neumol, CIPTIR, Monterrey, Mexico..
    Silva, D. Rossato
    Univ Fed Rio Grande do Sul, Fac Med, Porto Alegre, RS, Brazil..
    Ruslami, R.
    Univ Padjadjaran, Fac Med, TB HIV Res Ctr, Bandung, Indonesia.;Univ Padjadjaran, Fac Med, Dept Biomed Sci, Div Pharmacol & Therapy, Bandung, Indonesia..
    Saktiawati, A. M. I.
    Univ Gadjah Mada, Fac Med Publ Hlth & Nursing, Dept Internal Med, Yogyakarta, Indonesia.;Univ Gadjah Mada, Fac Med Publ Hlth & Nursing, Ctr Trop Med, Yogyakarta, Indonesia..
    Santoso, P.
    Univ Padjadjaran, Hasan Sadikin Gen Hosp, Fac Med, Dept Internal Med,Div Respirol & Crit Care, Bandung, Indonesia..
    Schaaf, H. S.
    Stellenbosch Univ, Desmond Tutu TB Ctr, Dept Paediat & Child Hlth, Tygerberg, South Africa..
    Seaworth, B.
    Univ Texas Hlth Sci Ctr Tyler, Tyler, TX USA..
    Simonsson, Ulrika S. H.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Singla, R.
    Natl Inst TB & Resp Dis, Dept TB & Resp Dis, New Delhi, India..
    Skrahina, A.
    Republican Res & Pract Ctr Pulmonol & TB, Minsk, BELARUS..
    Solovic, I.
    Catholic Univ, Natl Inst TB Lung Dis & Thorac Surg, Fac Hlth, , Vysne Hagy, Ruzomberok, Slovakia..
    Srivastava, S.
    Univ Texas Hlth Sci Ctr Tyler, Tyler, TX USA.;Univ Texas Tyler, Dept Med, Sch Med, Tyler, TX USA.;Texas Tech Univ, Dept Pharm Practice, Hlth Sci Ctr, Dallas, TX USA..
    Stocker, S. L.
    Univ Sydney, Fac Med & Hlth, Sch Pharm, Sydney, NSW, Australia.;St Vincents Hosp, Dept Clin Pharmacol & Toxicol, Sydney, NSW, Australia..
    Stukenboom, M. G. G.
    Univ Groningen, Univ Med Ctr Groningen, Dept Clin Pharm & Pharmacol, Groningen, Netherlands..
    Svensson, Elin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Radboud Univ Nijmegen, Res Inst Med Innovat, Dept Pharm, Med Ctr, Nijmegen, Netherlands..
    Tadolini, M.
    IRCCS Azienda Osped Univ Bologna, Infect Dis Unit, Policlin St Orsola, Bologna, Italy.;Alma Mater Studiorum Univ Bologna, Dept Med & Surg Sci, Bologna, Italy..
    Thomas, T. A.
    Univ Virginia, Div Infect Dis & Int Hlth, Charlottesville, VA USA..
    Tiberi, S.
    Queen Mary Univ London, Blizard Inst, Barts & London Sch Med & Dent, London, England..
    Trubiano, J.
    Univ Melbourne, Peter Doherty Inst Infect & Immun, Dept Infect Dis, Melbourne, Vic, Australia.;Austin Hosp, Dept Infect Dis, Melbourne, Vic, Australia..
    Udwadia, Z. F.
    PD Hinduja Natl Hosp & Med Res Ctr, Mumbai, India..
    Verhage, A. R.
    Univ Groningen, Univ Med Ctr Groningen, Dept Paediat, Groningen, Netherlands..
    Vu, D. H.
    Dept Pulm Dis & TB, Groningen, Netherlands..
    Akkerman, O. W.
    Univ Groningen, Univ Med Ctr Groningen, TB Ctr Beatrixoord, Haren, Netherlands.;Melbourne Hlth, Victorian TB Program, Melbourne, Vic, Australia..
    Alffenaar, J. W. C.
    Univ Sydney, Sydney Infecious Dis Inst Sydney ID, Sydney, NSW, Australia.;Westmead Hosp, Sydney, NSW, Australia.;Univ Sydney, Fac Med & Hlth, Sch Pharm, Sydney, NSW, Australia..
    Denholm, J. T.
    Univ Melbourne, Peter Doherty Inst Infect & Immun, Dept Infect Dis, Melbourne, Vic, Australia.;Royal Melbourne Hosp, Victorian Infect Dis Unit, Melbourne, Vic, Australia.;Univ Sydney, Sydney, NSW, Australia..
    Clinical standards for the management of adverse effects during treatment for TB2023In: The International Journal of Tuberculosis and Lung Disease, ISSN 1027-3719, E-ISSN 1815-7920, Vol. 27, no 7, p. 506-519Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Adverse effects (AE) to TB treatment cause morbidity, mortality and treatment interruption. The aim of these clinical standards is to encourage best practise for the diagnosis and management of AE.

    METHODS: 65/81 invited experts participated in a Delphi process using a 5-point Likert scale to score draft standards.

    RESULTS: We identified eight clinical standards. Each person commencing treatment for TB should: Standard 1, be counselled regarding AE before and during treatment; Standard 2, be evaluated for factors that might increase AE risk with regular review to actively identify and manage these; Standard 3, when AE occur, carefully assessed and possible allergic or hypersensitiv-ity reactions considered; Standard 4, receive appropriate care to minimise morbidity and mortality associated with AE; Standard 5, be restarted on TB drugs after a serious AE according to a standardised protocol that includes active drug safety monitoring. In addition: Standard 6, healthcare workers should be trained on AE including how to counsel people undertaking TB treatment, as well as active AE monitoring and management; Standard 7, there should be active AE monitoring and reporting for all new TB drugs and regimens; and Standard 8, knowledge gaps identified from active AE monitoring should be systematically addressed through clinical research.

    CONCLUSION: These standards provide a person -centred, consensus-based approach to minimise the impact of AE TB treatment.

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  • 45.
    Sonawane, Vidhisha V.
    et al.
    Radboud Univ Nijmegen Med Ctr, Radboudumc Ctr Infect Dis, Dept Med Microbiol, Nijmegen, Netherlands..
    Ruth, Mike M.
    Radboud Univ Nijmegen Med Ctr, Radboudumc Ctr Infect Dis, Dept Med Microbiol, Nijmegen, Netherlands..
    Pennings, Lian J.
    Radboud Univ Nijmegen Med Ctr, Radboudumc Ctr Infect Dis, Dept Med Microbiol, Nijmegen, Netherlands..
    Svensson, Elin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Radboud Univ Nijmegen Med Ctr, Radboudumc Ctr Infect Dis, Dept Pharm, Nijmegen, Netherlands.;Uppsala Univ, Dept Pharm, Uppsala, Sweden..
    Wertheim, Heiman F. L.
    Radboud Univ Nijmegen Med Ctr, Radboudumc Ctr Infect Dis, Dept Med Microbiol, Nijmegen, Netherlands..
    Hoefsloot, Wouter
    Radboud Univ Nijmegen Med Ctr, Radboudumc Ctr Infect Dis, Dept Pulm Dis, Nijmegen, Netherlands..
    van Ingen, Jakko
    Radboud Univ Nijmegen Med Ctr, Radboudumc Ctr Infect Dis, Dept Med Microbiol, Nijmegen, Netherlands..
    An In Vitro Perspective on What Individual Antimicrobials Add to Mycobacterium avium Complex Therapies2021In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 65, no 8, article id e02730-20Article in journal (Refereed)
    Abstract [en]

    For Mycobacterium avium complex pulmonary disease (MAC-PD), current treatment regimens yield low cure rates. To obtain an evidence-based combination therapy, we assessed the in vitro activity of six drugs, namely, clarithromycin (CLR), rifampin (RIF), ethambutol (EMB), amikacin (AMK), clofazimine (CLO), and minocycline (MIN), alone and in combination, against Mycobacterium avium and studied the contributions of individual antibiotics to efficacy. The MICs of all antibiotics against M. avium ATCC 700898 were determined by broth microdilution. We performed kinetic time-kill assays of all single drugs and clinically relevant two-, three-, four-, and five-drug combinations against M. avium. Pharmacodynamic interactions of these combinations were assessed using area under the time-kill curve-derived effect size and Bliss independence. Adding a second drug yielded an average increase of the effect size (E) of 18.7% +/- 32.9%, although antagonism was seen in some combinations. Adding a third drug showed a smaller increase in effect size (112.2% +/- 11.5%). The RIF-CLO-CLR (E of 102 log(10) CFU/ml . day), RIF-AMK-CLR (E of 101 log(10) CFU/ml . day), and AMK-MIN-EMB (E of 97.8 log(10) CFU/ml . day) regimens proved more active than the recommended RIF-EMB-CLR regimen (E of 89.1 log(10) CFU/ml . day). The addition of a fourth drug had little impact on effect size (+14.54% +/- 3.08%). In vitro, several two- and three-drug regimens are as effective as the currently recommended regimen for MAC-PD. Adding a fourth drug to any regimen had little additional effect. In vitro, the most promising regimen would be RIF-AMK-macrolide or RIF-CLO-macrolide.

  • 46.
    Stemkens, Ralf
    et al.
    Radboud Univ Nijmegen, Med Ctr, Dept Pharm, Nijmegen, Netherlands..
    de Jager, Veronique
    TASK, Cape Town, South Africa..
    Dawson, Rodney
    Univ Cape Town, Div Pulmonol, Cape Town, South Africa.;Univ Cape Town, Dept Med, Cape Town, South Africa.;Univ Cape Town, Lung Inst, Cape Town, South Africa..
    Diacon, Andreas H.
    TASK, Cape Town, South Africa..
    Narunsky, Kim
    Univ Cape Town, Div Pulmonol, Cape Town, South Africa.;Univ Cape Town, Dept Med, Cape Town, South Africa.;Univ Cape Town, Lung Inst, Cape Town, South Africa..
    Padayachee, Sherman D.
    Univ Cape Town, Div Pulmonol, Cape Town, South Africa.;Univ Cape Town, Dept Med, Cape Town, South Africa.;Univ Cape Town, Lung Inst, Cape Town, South Africa..
    Boeree, Martin J.
    Radboud Univ Nijmegen, Med Ctr, Dept Pulm Dis, Nijmegen, Netherlands..
    van Beek, Stijn W.
    Radboud Univ Nijmegen, Med Ctr, Dept Pharm, Nijmegen, Netherlands.
    Colbers, Angela
    Radboud Univ Nijmegen, Med Ctr, Dept Pharm, Nijmegen, Netherlands..
    Coenen, Marieke J. H.
    Erasmus Univ, Med Ctr, Rotterdam, Netherlands..
    Svensson, Elin M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Radboud Univ Nijmegen, Med Ctr, Dept Pharm, Nijmegen, Netherlands.
    Fuhr, Uwe
    Univ Cologne, Fac Med, Ctr Pharmacol, Clin Pharmacol,Dept Pharmacol 1, Cologne, Germany.;Univ Cologne, Univ Hosp Cologne, Cologne, Germany..
    Phillips, Patrick P. J.
    Univ Calif San Francisco, UCSF Ctr TB, San Francisco, CA USA..
    te Brake, Lindsey H. M.
    Radboud Univ Nijmegen, Med Ctr, Dept Pharm, Nijmegen, Netherlands..
    Aarnoutse, Rob E.
    Radboud Univ Nijmegen, Med Ctr, Dept Pharm, Nijmegen, Netherlands..
    Drug interaction potential of high-dose rifampicin in patients with pulmonary tuberculosis2023In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 67, no 10, article id e0068323Article in journal (Refereed)
    Abstract [en]

    Accumulating evidence supports the use of higher doses of rifampicin for tuberculosis (TB) treatment. Rifampicin is a potent inducer of metabolic enzymes and drug transporters, resulting in clinically relevant drug interactions. To assess the drug interaction potential of higher doses of rifampicin, we compared the effect of high-dose rifampicin (40 mg/kg daily, RIF40) and standard-dose rifampicin (10 mg/kg daily, RIF10) on the activities of major cytochrome P450 (CYP) enzymes and P-glycoprotein (P-gp). In this open-label, single-arm, two-period, fixed-order phenotyping cocktail study, adult participants with pulmonary TB received RIF10 (days 1–15), followed by RIF40 (days 16–30). A single dose of selective substrates (probe drugs) was administered orally on days 15 and 30: caffeine (CYP1A2), tolbutamide (CYP2C9), omeprazole (CYP2C19), dextromethorphan (CYP2D6), midazolam (CYP3A), and digoxin (P-gp). Intensive pharmacokinetic blood sampling was performed over 24 hours after probe drug intake. In all, 25 participants completed the study. Geometric mean ratios (90% confidence interval) of the total exposure (area under the concentration versus time curve, RIF40 versus RIF10) for each of the probe drugs were as follows: caffeine, 105% (96%–115%); tolbutamide, 80% (74%–86%); omeprazole, 55% (47%–65%); dextromethorphan, 77% (68%–86%); midazolam, 62% (49%–78%), and 117% (105%–130%) for digoxin. In summary, high-dose rifampicin resulted in no additional effect on CYP1A2, mild additional induction of CYP2C9, CYP2C19, CYP2D6, and CYP3A, and marginal inhibition of P-gp. Existing recommendations on managing drug interactions with rifampicin can remain unchanged for the majority of co-administered drugs when using high-dose rifampicin. Clinical Trials registration number NCT04525235.

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  • 47.
    Sturkenboom, Marieke G. G.
    et al.
    Univ Groningen, Univ Med Ctr Groningen, Dept Clin Pharm & Pharmacol, Groningen, Netherlands..
    Martson, Anne-Grete
    Univ Groningen, Univ Med Ctr Groningen, Dept Clin Pharm & Pharmacol, Groningen, Netherlands..
    Svensson, Elin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Uppsala Univ, Dept Pharm, Uppsala, Sweden.;Radboud Univ Nijmegen Med Ctr, Radboud Inst Hlth Sci, Dept Pharm, Nijmegen, Netherlands..
    Sloan, Derek J.
    Univ Liverpool, Inst Infect & Global Hlth, Liverpool, Merseyside, England.;Univ Liverpool Liverpool Sch Trop Med, Liverpool, Merseyside, England.;Univ St Andrews, Sch Med, St Andrews, Fife, Scotland..
    Dooley, Kelly E.
    Johns Hopkins Univ, Sch Med, Dept Med, Ctr TB Res, Baltimore, MD 21205 USA..
    van den Elsen, Simone H. J.
    Univ Groningen, Univ Med Ctr Groningen, Dept Clin Pharm & Pharmacol, Groningen, Netherlands.;Hosp Grp Twente, Dept Clin Pharm, Almelo, Hengelo, Netherlands..
    Denti, Paolo
    Univ Cape Town, Div Clin Pharmacol, Dept Med, Cape Town, South Africa..
    Peloquin, Charles A.
    Univ Florida, Coll Pharm, Dept Pharmacotherapy & Translat Res, Gainesville, FL USA..
    Aarnoutse, Rob E.
    Radboud Univ Nijmegen Med Ctr, Radboud Inst Hlth Sci, Dept Pharm, Nijmegen, Netherlands..
    Alffenaar, Jan-Willem C.
    Univ Groningen, Univ Med Ctr Groningen, Dept Clin Pharm & Pharmacol, Groningen, Netherlands.;Univ Sydney, Sch Pharm, Fac Med & Hlth, Pharm Bldg A15, Sydney, NSW 2006, Australia.;Westmead Hosp, Westmead, NSW, Australia.;Univ Sydney, Marie Bashir Inst Infect Dis & Biosecur, Sydney, NSW, Australia..
    Population Pharmacokinetics and Bayesian Dose Adjustment to Advance TDM of Anti-TB Drugs2021In: Clinical Pharmacokinetics, ISSN 0312-5963, E-ISSN 1179-1926, Vol. 60, no 6, p. 685-710Article, review/survey (Refereed)
    Abstract [en]

    Tuberculosis (TB) is still the number one cause of death due to an infectious disease. Pharmacokinetics and pharmacodynamics of anti-TB drugs are key in the optimization of TB treatment and help to prevent slow response to treatment, acquired drug resistance, and adverse drug effects. The aim of this review was to provide an update on the pharmacokinetics and pharmacodynamics of anti-TB drugs and to show how population pharmacokinetics and Bayesian dose adjustment can be used to optimize treatment. We cover aspects on preclinical, clinical, and population pharmacokinetics of different drugs used for drug-susceptible TB and multidrug-resistant TB. Moreover, we include available data to support therapeutic drug monitoring of these drugs and known pharmacokinetic and pharmacodynamic targets that can be used for optimization of therapy. We have identified a wide range of population pharmacokinetic models for first- and second-line drugs used for TB, which included models built on NONMEM, Pmetrics, ADAPT, MWPharm, Monolix, Phoenix, and NPEM2 software. The first population models were built for isoniazid and rifampicin; however, in recent years, more data have emerged for both new anti-TB drugs, but also for defining targets of older anti-TB drugs. Since the introduction of therapeutic drug monitoring for TB over 3 decades ago, further development of therapeutic drug monitoring in TB next steps will again depend on academic and clinical initiatives. We recommend close collaboration between researchers and the World Health Organization to provide important guideline updates regarding therapeutic drug monitoring and pharmacokinetics/pharmacodynamics.

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  • 48.
    Susanto, Budi O.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Svensson, Elin M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Radboud Univ Nijmegen Med Ctr, Radboud Inst Hlth Sci, Dept Pharm, Nijmegen, Netherlands.
    te Brake, Lindsey
    Radboud Univ Nijmegen Med Ctr, Radboud Inst Hlth Sci, Dept Pharm, Nijmegen, Netherlands..
    Aarnoutse, Rob E.
    Radboud Univ Nijmegen Med Ctr, Radboud Inst Hlth Sci, Dept Pharm, Nijmegen, Netherlands..
    Boeree, Martin J.
    Radboud Univ Nijmegen Med Ctr, Radboud Inst Hlth Sci, Dept Pulm Dis, Nijmegen, Netherlands..
    Simonsson, Ulrika S. H.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Model-based analysis of bactericidal activity and a new dosing strategy for optimised-dose rifampicin2023In: International Journal of Antimicrobial Agents, ISSN 0924-8579, E-ISSN 1872-7913, Vol. 61, no 6, article id 106813Article in journal (Refereed)
    Abstract [en]

    Background

    Higher doses of rifampicin for tuberculosis have been shown to improve early bactericidal activity (EBA) and at the same time increase the intolerability due to high exposure at the beginning of treatment. To support dose optimisation of rifampicin, this study investigated new and innovative staggered dosing of rifampicin using clinical trial simulations to minimise tolerability problems and still achieve good efficacy.

    Methods

    Rifampicin population pharmacokinetics and time-to-positivity models were applied to data from patients receiving 14 days of daily 10–50 mg/kg rifampicin to characterise the exposure-response relationship. Furthermore, clinical trial simulations of rifampicin exposure were performed following four different staggered dosing scenarios. The simulated exposure after 35 mg/kg was used as a relative comparison for efficacy. Tolerability was derived from a previous model-based analysis relating exposure at day 7 and the probability of having adverse events.

    Results

    The linear relationship between rifampicin exposure and bacterial killing rate in sputum indicated that the maximum rifampicin EBA was not reached at doses up to 50 mg/kg. Clinical trial simulations of a staggered dosing strategy starting the treatment at a lower dose (20 mg/kg) for 7 days followed by a higher dose (40 mg/kg) predicted a lower initial exposure with lower probability of tolerability problems and better EBA compared with a regimen of 35 mg/kg daily.

    Conclusions

    Staggered dosing of 20 mg/kg for 7 days followed by 40 mg/kg is predicted to reduce tolerability while maintaining exposure levels associated with better efficacy.

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  • 49.
    Susanto, Budi Octasari
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Svensson, Robin J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Svensson, Elin M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Department of Pharmacy, Radboud Institute for Health Sciences, Radboud University Medical Center , Nijmegen, The Netherlands.
    Aarnoutse, Rob
    Department of Pharmacy, Radboud Institute for Health Sciences, Radboud University Medical Center , Nijmegen, The Netherlands.
    Boeree, Martin J
    Department of Pharmacy, Radboud Institute for Health Sciences, Radboud University Medical Center , Nijmegen, The Netherlands.
    Simonsson, Ulrika S. H.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Rifampicin can be given as flat-dosing instead of weight-band dosing2020In: Clinical Infectious Diseases, ISSN 1058-4838, E-ISSN 1537-6591, Vol. 71, no 12, p. 3055-3060, article id ciz1202Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The weight-band dosing in tuberculosis treatment regimen has been implemented in clinical practice for decades. Patients will receive different number of fixed dose combination (FDC) tablets according to their weight-band. However, some analysis have shown that weight was not the best covariate to explain variability of rifampicin exposure. Furthermore, the rationale for using weight-band dosing instead of flat-dosing becomes questionable. Therefore, this study aimed to compare the average and the variability of rifampicin exposure after weight-band dosing and flat-dosing.

    METHODS: Rifampicin exposure were simulated using previously published population pharmacokinetics model at dose 10-40 mg/kg for weight-band dosing and dose 600-2400 mg for flat-dosing. The median AUC0-24h after day 7 and 14 were compared as well as the variability of each dose group between weight-band and flat-dosing.

    RESULTS: The difference of median AUC0-24h of all dose groups between flat-dosing and weight-band dosing were considered low (< 20%) except for the lowest dose. At the dose of 10 mg/kg (600 mg for flat-dosing), flat-dosing resulted in higher median AUC0-24h compared to the weight-band dosing. A marginal decrease in between-patient variability was predicted for weight-band dosing compared to flat-dosing.

    CONCLUSIONS: Weight-band dosing yields a small and non-clinically relevant decrease in variability of AUC0-24h.

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  • 50.
    Svensson, Elin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Radboud Univ Nijmegen Med Ctr, Radboud Inst Hlth Sci, Dept Pharm, Nijmegen, Netherlands.
    du Bois, Jeannine
    TASK Appl Sci, Cape Town, South Africa.
    Kitshoff, Rene
    TASK Appl Sci, Cape Town, South Africa.
    de Jager, Veronique R.
    TASK Appl Sci, Cape Town, South Africa.
    Wiesner, Lubbe
    Univ Cape Town, Div Clin Pharmacol, Dept Med, Cape Town, South Africa.
    Norman, Jennifer
    Univ Cape Town, Div Clin Pharmacol, Dept Med, Cape Town, South Africa.
    Nachman, Sharon
    SUNY Stony Brook, Dept Pediat, Stony Brook, NY 11794 USA.
    Smith, Betsy
    NIAID, Div Aids, NIH, Bethesada, MA USA.
    Diacon, Andreas H.
    TASK Appl Sci, Cape Town, South Africa;Stellenbosch Univ, Div Med Physiol, Fac Med & Hlth Sci, Stellenbosch, South Africa.
    Hesseling, Anneke C.
    Stellenbosch Univ, Dept Paediat & Child Hlth, Desmond Tutu TB Ctr, Fac Med & Hlth Sci, Cape Town, South Africa.
    Garcia-Prats, Anthony J.
    Stellenbosch Univ, Dept Paediat & Child Hlth, Desmond Tutu TB Ctr, Fac Med & Hlth Sci, Cape Town, South Africa.
    Relative bioavailability of bedaquiline tablets suspended in water: Implications for dosing in children2018In: British Journal of Clinical Pharmacology, ISSN 0306-5251, E-ISSN 1365-2125, Vol. 84, no 10, p. 2384-2392Article in journal (Refereed)
    Abstract [en]

    Aims: Bedaquiline is an important novel drug for treatment of multidrug-resistant tuberculosis, but no paediatric formulation is yet available. This work aimed to explore the possibility of using the existing tablet formulation in children by evaluating the relative bioavailability, short-term safety, acceptability and palatability of suspended bedaquiline tablets compared to whole tablets.

    Methods: A randomized, open-label, two-period cross-over study was conducted in 24 healthy adult volunteers. Rich pharmacokinetic sampling over 48h was conducted at two occasions 14days apart in each participant after administration of 400mg bedaquiline (whole or suspended in water). The pharmacokinetic data were analysed with nonlinear mixed-effects modelling. A questionnaire was used to assess palatability and acceptability.

    Results: There was no statistically significant difference in the bioavailability of the suspended bedaquiline tables compared to whole. The nonparametric 95% confidence interval of the relative bioavailability of suspended bedaquiline tablets was 94-108% of that of whole bedaquiline tablets; hence, the predefined bioequivalence criteria were fulfilled. There were no Grade 3 or 4 or serious treatment emergent adverse events recorded in the study and no apparent differences between whole tablets and suspension regarding taste, texture or smell.

    Conclusions: The bioavailability of bedaquiline tablets suspended in water was the same as for tablets swallowed whole and the suspension was well tolerated. This suggests that the currently available bedaquiline formulation could be used to treat multidrug-resistant tuberculosis in children, to bridge the gap between when paediatric dosing regimens have been established and when a paediatric dispersible formulation is routinely available.

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