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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..