M. Chetty, T. Cain, M. Jamei, A. Rostami; Simcyp, Sheffield, United Kingdom

BACKGROUND: Serious adverse reactions to a standard 600 mg of efavirenz have been reported in poor metabolizers (PMs) of CYP2B6, the major enzyme responsible for efavirenz metabolism. The objective of this study was to determine whether a standard dose of efavirenz can be useful as a probe drug in identifying PMs, when genotyping is unavailable.
METHODS: Prior in vitro data were used to develop a physiologically based pharmacokinetic (PBPK) model to simulate the pharmacokinetics of a 600 mg dose of efavirenz in extensive metabolizers (EMs), intermediate metabolizers (IMs) and PMs of CYP2B6, using the Simcyp population-based simulator (V13 R2). After verifying the performance of the models with observed data, the models were used to simulate 5,000 virtual individuals in each category. Simulated concentration-time data were then used as a training set in a Bayesian model that was developed to determine the probability of identifying each phenotype based on plasma concentrations of efavirenz. Sampling times of 2 hr, 4 hr, 8 hr, 12 hr and 24 hr for a single dose and 24 hr post dose for multiple dosing were tested to determine which sampling time was associated with the highest probability of identifying PMs. The predictive capacity of the final Bayesian model was tested using published clinical data.
RESULTS: Performance of the developed models was acceptable. Application of the Bayesian model suggested that there was a good likelihood of differentiating between the three phenotypes and in particular the probability of correctly identifying a PM phenotype was 0.82, corresponding to the 24 hr single dose sample.
CONCLUSION: This approach may be useful in identifying patients who are at risk of experiencing serious adverse reactions and require dosage adjustments.