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  • 1.
    Brill, Margreke J. E.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Kristoffersson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Zhao, Chenyan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Nielsen, Elisabet I.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Friberg, Lena E
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Semi-mechanistic pharmacokinetic-pharmacodynamic modelling of antibiotic drug combinations2018In: Clinical Microbiology and Infection, ISSN 1198-743X, E-ISSN 1469-0691, Vol. 24, no 7, p. 697-706Article, review/survey (Refereed)
    Abstract [en]

    Background: Deriving suitable dosing regimens for antibiotic combination therapy poses several challenges as the drug interaction can be highly complex, the traditional pharmacokinetic-pharmacodynamic (PKPD) index methodology cannot be applied straightforwardly, and exploring all possible dose combinations is unfeasible. Therefore, semi-mechanistic PKPD models developed based on in vitro single and combination experiments can be valuable to suggest suitable combination dosing regimens. Aims: To outline how the interaction between two antibiotics has been characterized in semi-mechanistic PKPD models. We also explain how such models can be applied to support dosing regimens and design future studies. Sources: PubMed search for published semi-mechanistic PKPD models of antibiotic drug combinations. Content: Thirteen publications were identified where ten had applied subpopulation synergy to characterize the combined effect, i.e. independent killing rates for each drug and bacterial subpopulation. We report the various types of interaction functions that have been used to describe the combined drug effects and that characterized potential deviations from additivity under the PKPD model. Simulations from the models had commonly been performed to compare single versus combined dosing regimens and/or to propose improved dosing regimens.

  • 2.
    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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  • 3.
    Brussee, Janneke M.
    et al.
    Leiden Univ, LACDR, Div Syst Biomed & Pharmacol, Leiden, Netherlands.
    Yu, Huixin
    Leiden Univ, LACDR, Div Syst Biomed & Pharmacol, Leiden, Netherlands.
    Krekels, Elke H. J.
    Leiden Univ, LACDR, Div Syst Biomed & Pharmacol, Leiden, Netherlands.
    de Roos, Berend
    Leiden Univ, LACDR, Div Syst Biomed & Pharmacol, Leiden, Netherlands.
    Brill, Margreke JE
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    van den Anker, Johannes N.
    Univ Basel, Childrens Hosp, Div Paediat Pharmacol & Pharmacometr, Basel, Switzerland;Sophia Childrens Univ Hosp, Erasmus MC, Intens Care & Dept Pediat Surg, Rotterdam, Netherlands;Childrens Natl Hlth Syst, Div Clin Pharmacol, Washington, DC USA.
    Rostami-Hodjegan, Amin
    Simcyp Ltd, Sheffield, S Yorkshire, England;Univ Manchester, Ctr Appl Pharmacokinet Res, Manchester, Lancs, England.
    de Wildt, Saskia N.
    Radboud Univ Nijmegen, Dept Pharmacol & Toxicol, Med Ctr, Nijmegen, Netherlands;Sophia Childrens Univ Hosp, Erasmus MC, Intens Care & Dept Pediat Surg, Rotterdam, Netherlands.
    Knibbe, Catherijne A. J.
    Leiden Univ, LACDR, Div Syst Biomed & Pharmacol, Leiden, Netherlands;St Antonius Hosp, Dept Clin Pharm, Nieuwegein, Netherlands.
    First-Pass CYP3A-Mediated Metabolism of Midazolam in the Gut Wall and Liver in Preterm Neonates2018In: CPT: Pharmacometrics and Systems Pharmacology (PSP), E-ISSN 2163-8306, Vol. 7, no 6, p. 374-383Article in journal (Refereed)
    Abstract [en]

    To predict first-pass and systemic cytochrome P450 (CYP) 3A-mediated metabolism of midazolam in preterm neonates, a physiological population pharmacokinetic model was developed describing intestinal and hepatic midazolam clearance in preterm infants. On the basis of midazolam and 1-OH-midazolam concentrations from 37 preterm neonates (gestational age 26-34 weeks) receiving midazolam orally and/or via a 30-minute intravenous infusion, intrinsic clearance in the gut wall and liver were found to be very low, with lower values in the gut wall (0.0196 and 6.7 L/h, respectively). This results in a highly variable and high total oral bioavailability of 92.1% (range, 67-95%) in preterm neonates, whereas this is around 30% in adults. This approach in which intestinal and hepatic clearance were separately estimated shows that the high bioavailability in preterm neonates is explained by, likely age-related, low CYP3A activity in the liver and even lower CYP3A activity in the gut wall.

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  • 4.
    Brussee, Janneke M.
    et al.
    Leiden Univ, LACDR, Div Syst Biomed & Pharmacol, Leiden, Netherlands.
    Yu, Huixin
    Novartis, Basel, Switzerland;Leiden Univ, LACDR, Div Syst Biomed & Pharmacol, Leiden, Netherlands.
    Krekels, Elke H. J.
    Leiden Univ, LACDR, Div Syst Biomed & Pharmacol, Leiden, Netherlands.
    Palic, Semra
    Netherlands Canc Inst NKI, Amsterdam, Netherlands;Leiden Univ, LACDR, Div Syst Biomed & Pharmacol, Leiden, Netherlands.
    Brill, Margreke J.E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Barrett, Jeffrey S.
    Sanofi, Translat Informat, Bridgewater, NJ USA;Childrens Hosp Philadelphia, Dept Pediat, Div Clin Pharmacol & Therapeut, Philadelphia, PA 19104 USA.
    Rostami-Hodjegan, Amin
    Univ Manchester, Ctr Appl Pharmacokinet Res, Manchester, Lancs, England;Simcyp Ltd, Sheffield, S Yorkshire, England.
    de Wildt, Saskia N.
    Erasmus MC Sophia Childrens Hosp, Dept Pediat Surg, Rotterdam, Netherlands;Radboud Univ Nijmegen, Dept Pharmacol & Toxicol, Med Ctr, Nijmegen, Netherlands;Erasmus MC Sophia Childrens Hosp, Intens Care, Rotterdam, Netherlands.
    Knibbe, Catherijne A. J.
    St Antonius Hosp, Dept Clin Pharm, Nieuwegein, Netherlands;Leiden Univ, LACDR, Div Syst Biomed & Pharmacol, Leiden, Netherlands.
    Characterization of Intestinal and Hepatic CYP3A-Mediated Metabolism of Midazolam in Children Using a Physiological Population Pharmacokinetic Modelling Approach2018In: Pharmaceutical research, ISSN 0724-8741, E-ISSN 1573-904X, Vol. 35, no 9, article id 182Article in journal (Refereed)
    Abstract [en]

    Purpose Changes in drug absorption and first-pass metabolism have been reported throughout the pediatric age range. Our aim is to characterize both intestinal and hepatic CYP3A-mediated metabolism of midazolam in children in order to predict first-pass and systemic metabolism of CYP3A substrates. Methods Pharmacokinetic (PK) data of midazolam and 1-OH-midazolam from 264 post-operative children 1-18 years of age after oral administration were analyzed using a physiological population PK. modelling approach. In the model, consisting of physiological compartments representing the gastro-intestinal tract and liver,intrinsic intestinal and hepatic clearances were estimated to derive values for bioavailability and plasma clearance. Results The whole-organ intrinsic clearance in the gut wall and liver were found to increase with body weight, with a 105 (95% confidence interval (CI): 5-405) times lower intrinsic gut wall clearance than the intrinsic hepatic dearance (i.e. 5.08 L/h (relative standard error (RSE) 10%) versus 527 L/h (RSE 7%) for a 16 kg individual, respectively). When expressed per gram of organ, intrinsic clearance increases with increasing body weight in the gut wall, but decreases in the liver, indicating that CYP3A-mediated intrinsic clearance and local bioavailability in the gut wall and liver do not change with age in parallel. The resulting total bioavailability was found to be age-independent with a median of 20.8% in children (95%CI: 3.8-50.0%). Conclusion In conclusion, the intrinsic CYP3A-mediated gut wall clearance is substantially lower than the intrinsic hepatic CYP3A-mediated clearance in children from 1 to 18 years of age, and contributes less to the overall first-pass metabolism compared to adults.

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  • 5.
    Kristoffersson, Anders N.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Rognås, Viktor
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Brill, Margreke JE
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Dishon-Benattar, Y
    Durante-Mangoni, E
    Daitch, V
    Skiada, A
    Lellouche, J
    Nutman, A
    Kotsaki, A
    Andini, R
    Eliakim-Raz, N
    Bitterman, R
    Antoniadou, A
    Karlsson, M O
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Theuretzbacher, U
    Leibovici, L
    Daikos, G L
    Mouton, J W
    Carmeli, Y
    Paul, M
    Friberg, Lena E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Population pharmacokinetics of colistin and the relation to survival in critically ill patients infected with colistin susceptible and carbapenem-resistant bacteria2020In: Clinical Microbiology and Infection, ISSN 1198-743X, E-ISSN 1469-0691, Vol. 26, no 12, p. 1644-1650Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: The aim was to analyse the population pharmacokinetics of colistin and to explore the relationship between colistin exposure and time to death.

    METHODS: Patients included in the AIDA randomized controlled trial were treated with colistin for severe infections caused by carbapenem-resistant Gram-negative bacteria. All subjects received a 9 million units (MU) loading dose, followed by a 4.5 MU twice daily maintenance dose, with dose reduction if creatinine clearance (CrCL) < 50 mL/min. Individual colistin exposures were estimated from the developed population pharmacokinetic model and an optimized two-sample per patient sampling design. Time to death was evaluated in a parametric survival analysis.

    RESULTS: Out of 406 randomized patients, 349 contributed pharmacokinetic data. The median (90% range) colistin plasma concentration was 0.44 (0.14-1.59) mg/L at 15 minutes after the end of first infusion. In samples drawn 10 hr after a maintenance dose, concentrations were >2 mg/L in 94% (195/208) and 44% (38/87) of patients with CrCL ≤120 mL/min, and >120 mL/min, respectively. Colistin methanesulfonate sodium (CMS) and colistin clearances were strongly dependent on CrCL. High colistin exposure to MIC ratio was associated with increased hazard of death in the multivariate analysis (adjusted hazard ratio (95% CI): 1.07 (1.03-1.12)). Other significant predictors included SOFA score at baseline (HR 1.24 (1.19-1.30) per score increase), age and Acinetobacter or Pseudomonas as index pathogen.

    DISCUSSION: The population pharmacokinetic model predicted that >90% of the patients had colistin concentrations >2 mg/L at steady state, but only 66% at 4 hr after start of treatment. High colistin exposure was associated with poor kidney function, and was not related to a prolonged survival.

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  • 6.
    van Rongen, Anne
    et al.
    St Antonius Hosp, Dept Clin Pharm, Koekoekslaan 1, NL-3435 CM Nieuwegein, Netherlands;Leiden Univ, Leiden Acad Ctr Drug Res, Div Pharmacol, Leiden, Netherlands;Reinier de Graaf Hosp, Dept Clin Pharm, Delft, Netherlands.
    Brill, Margreke JE
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. St Antonius Hosp, Dept Clin Pharm, Koekoekslaan 1, NL-3435 CM Nieuwegein, Netherlands;Leiden Univ, Leiden Acad Ctr Drug Res, Div Pharmacol, Leiden, Netherlands.
    Vaughns, Janelle D.
    Childrens Natl Hlth Syst, Div Anesthesiol & Pain Med, Washington, DC USA;Childrens Natl Hlth Syst, Div Clin Pharmacol, Washington, DC USA.
    Valitalo, Pyry A. J.
    Leiden Univ, Leiden Acad Ctr Drug Res, Div Pharmacol, Leiden, Netherlands.
    van Dongen, Eric P. A.
    St Antonius Hosp, Dept Anesthesiol & Intens Care, Nieuwegein, Netherlands.
    van Ramshorst, Bert
    St Antonius Hosp, Dept Surg, Nieuwegein, Netherlands.
    Barrett, Jeffrey S.
    Childrens Hosp Philadelphia, Lab Appl PK PD, Philadelphia, PA 19104 USA.
    van den Anker, Johannes N.
    Childrens Natl Hlth Syst, Div Clin Pharmacol, Washington, DC USA;Univ Childrens Hosp, Div Pediat Pharmacol & Pharmacometr, Basel, Switzerland;Sophia Childrens Univ Hosp, Erasmus MC, Intens Care, Rotterdam, Netherlands;Sophia Childrens Univ Hosp, Erasmus MC, Dept Pediat Surg, Rotterdam, Netherlands.
    Knibbe, Catherijne A. J.
    St Antonius Hosp, Dept Clin Pharm, Koekoekslaan 1, NL-3435 CM Nieuwegein, Netherlands;Leiden Univ, Leiden Acad Ctr Drug Res, Div Pharmacol, Leiden, Netherlands.
    Higher Midazolam Clearance in Obese Adolescents Compared with Morbidly Obese Adults2018In: Clinical Pharmacokinetics, ISSN 0312-5963, E-ISSN 1179-1926, Vol. 57, no 5, p. 601-611Article in journal (Refereed)
    Abstract [en]

    Background

    The clearance of cytochrome P450 (CYP) 3A substrates is reported to be reduced with lower age, inflammation and obesity. As it is unknown what the overall influence is of these factors in the case of obese adolescents vs. morbidly obese adults, we studied covariates influencing the clearance of the CYP3A substrate midazolam in a combined analysis of data from obese adolescents and morbidly obese adults.

    Methods

    Data from 19 obese adolescents [102.7 kg (62-149.5 kg)] and 20 morbidly obese adults [144 kg (112-186 kg)] receiving intravenous midazolam were analysed, using population pharmacokinetic modelling (NONMEM 7.2). In the covariate analysis, the influence of study group, age, total body weight (TBW), developmental weight (WTfor age and length) and excess body weight (WTexcess = TBW - WTfor age and length) was evaluated.

    Results

    The population mean midazolam clearance was significantly higher in obese adolescents than in morbidly obese adults [0.71 (7%) vs. 0.44 (11%) L/min; p < 0.01]. Moreover, clearance in obese adolescents increased with TBW (p < 0.01), which seemed mainly explained by WTexcess, and for which a so-called 'excess weight' model scaling WTfor age and length to the power of 0.75 and a separate function for WTexcess was proposed.

    Discussion

    We hypothesise that higher midazolam clearance in obese adolescents is explained by less obesity-induced suppression of CYP3A activity, while the increase with WTexcess is explained by increased liver blood flow. The approach characterising the influence of obesity in the paediatric population we propose here may be of value for use in future studies in obese adolescents.

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