Application of Physiologically Based Pharmacokinetic (PBPK) Modeling Within a Bayesian Framework to Identify Poor Metabolizers of Efavirenz (PM), Using a Test Dose of Efavirenz

Manoranjenni Chetty, Theresa Cain, Janak Wedagedera, Amin Rostami-Hodjegan, Masoud Jamei

Poor metabolisers of CYP2B6 (PM) require a lower dose of efavirenz because of serious adverse reactions resulting from the higher plasma concentrations associated with a standard dose. Treatment discontinuation is a common consequence in patients experiencing these adverse reactions. Such patients benefit from appropriate dose reduction, where efficacy can be achieved without the serious adverse reactions. PMs are usually identified by genotyping. However, in countries with limited resources genotyping is unaffordable. Alternative cost-effective methods of identifying a PM will be highly beneficial. This study was designed to determine whether a plasma concentration corresponding to a 600 mg test dose of efavirenz can be used to identify a PM. A physiologically based pharmacokinetic (PBPK) model was used to simulate the concentration-time profiles of a 600 mg dose of efavirenz in extensive metabolizers (EM), intermediate metabolizers (IM), and PM of CYP2B6. Simulated concentration-time data were used in a Bayesian framework to determine the probability of identifying a PM, based on plasma concentrations of efavirenz at a specific collection time. Results indicated that there was a high likelihood of differentiating a PM from other phenotypes by using a 24 h plasma concentration. The probability of correctly identifying a PM phenotype was 0.82 (true positive), while the probability of not identifying any other phenotype as a PM (false positive) was 0.87. A plasma concentration >1,000 ng/mL at 24 h post-dose is likely to be from a PM. Further verification of these findings using clinical studies is recommended.