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

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Date
2010Author
Rekic´, Dinko
Röshammar, Daniel
Mukonzo, Jackson K
Ashton, Michael
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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.