Article date: April 2011
By: Dinko Rekić, Daniel Röshammar, Jackson Mukonzo, Michael Ashton, in Volume 71, Issue 4, pages 536-543
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT
• Rifampicin is known to reduce the exposure of efavirenz. Despite lack of adequate clinical support, most guidelines recommend an increased efavirenz dose in patients treated with both drugs, although some propose an increase only in patients weighing over 50 kg.
WHAT THIS STUDY ADDS
• An example of utilization of in vitro data to predict in vivo consequences of metabolic drug–drug interactions, suggesting answers to specific questions difficult to study in patients. Here the efavirenz–rifampicin interaction was simulated with the specific question of whether or not to increase the efavirenz dose based on bodyweight.
• The results from this simulation suggest that increasing the efavirenz dose may be appropriate only in patients with bodyweights over 50 kg.
AIMS 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.
DOI: 10.1111/j.1365-2125.2010.03883.x
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