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dc.contributor.authorRekic´, Dinko
dc.contributor.authorRöshammar, Daniel
dc.contributor.authorMukonzo, Jackson K
dc.contributor.authorAshton, Michael
dc.date.accessioned2012-07-31T14:48:43Z
dc.date.available2012-07-31T14:48:43Z
dc.date.issued2010
dc.identifier.citationRekic´, D., Röshammar, D., Mukonzo, J.K., Ashton, M. (2010). In silico prediction of efavirenz and rifampicin drug–drug interaction considering weight and CYP2B6 phenotype. British Journal of Clinical Pharmacology, 71(4)en_US
dc.identifier.urihttp://hdl.handle.net/10570/642
dc.description.abstractAIMS This study aimed to test whether a pharmacokinetic simulation model could extrapolate nonclinical 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% confidence interval 13–19) in efavirenz area under the concentration–time curve, of the same magnitude as 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. CONCLUSIONS 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.en_US
dc.language.isoenen_US
dc.publisherThe British Pharmacological Societyen_US
dc.subjectDrug–drug interactionen_US
dc.subjectEfavirenzen_US
dc.subjectHIV/AIDSen_US
dc.subjectIn vitro–in vivo extrapolationen_US
dc.subjectRifampicinen_US
dc.subjectSimcypen_US
dc.subjectHighly active antiretroviral therapy (HAART)en_US
dc.titleIn silico prediction of efavirenz and rifampicin drug–drug interaction considering weight and CYP2B6 phenotypeen_US
dc.typeJournal article, peer revieweden_US


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