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In silico prediction of efavirenz and rifampicin drug-drug interaction considering weight and CYP2B6 phenotype

Journal article
Authors Dinko Rekić
Daniel Röshammar
Jackson Mukonzo
Michael Ashton
Published in British Journal of Clinical Pharmacology
Volume 71
Issue 4
Pages 536-43
ISSN 0306-5251
Publication year 2011
Published at Institute of Neuroscience and Physiology, Department of Pharmacology
Pages 536-43
Language en
Keywords efavirenz;drug-drug interaction;rifampicin;in vitro in vivo extrapolation;Simcyp;HIV/AIDS;Anti-HIV Agents, pharmacokinetics, therapeutic use, Antibiotics, Antitubercular, pharmacokinetics, therapeutic use, Aryl Hydrocarbon Hydroxylases, genetics, Benzoxazines, pharmacokinetics, therapeutic use, Body Weight, drug effects, Computer Simulation, Dose-Response Relationship, Drug, Drug Interactions, Drug Therapy, Combination, Forecasting, methods, HIV Infections, drug therapy, genetics, Humans, Models, Theoretical, Oxidoreductases, N-Demethylating, genetics, Phenotype, Rifampin, pharmacokinetics, therapeutic use, Tuberculosis, drug therapy, genetics
Subject categories Numerical analysis, Mathematical statistics, Pharmacy, Clinical pharmacology, Pharmaceutical pharmacology, Infectious Medicine


Aims: To test whether a pharmacokinetic simulation model could extrapolate non-clinical drug data to predict human efavirenz exposure after single and continuous dosing as well as the effects of concomitant rifampicin and further to evaluate the weight based dosage recommendations used to counteract the rifampicin-efavirenz interaction. Methods: Efavirenz pharmacokinetics were simulated using a physiologically-based pharmacokinetic model implemented in the Simcyp population-based simulator. Physicochemical and metabolism data obtained from the literature were used as input for prediction of pharmacokinetic parameters. The model was used to simulate the effects of rifampicin on efavirenz pharmacokinetics in 400 virtual patients, taking into account bodyweight and CYP2B6 phenotype. Results: Apart from the absorption phase, the simulation model predicted efavirenz concentration-time profiles reasonably well with close agreement with clinical data. The simulated effects of rifampicin co-administration on efavirenz treatment showed only a minor decrease of 16% (95%CI 13; 19) in efavirenz area under the concentration-time curve (AUC), in magnitude with what has been clinically observed (22%). Efavirenz exposure depended on CYP2B6 phenotype and bodyweight. Increasing the efavirenz dose during concomitant rifampicin was predicted to be most successful in patients over 50 kg regardless of CYP2B6 status. Conclusion: Our findings, although based on a simulation approach using limited in vitro data, support the current recommendations for using a 50 kg bodyweight cut-off for efavirenz dose increment when co-treating with rifampicin.

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