A Population Pharmacokinetic Approach to Understand the Effect of Efavirenz on CYP3A Activity in Healthy Volunteers Using Midazolam as a Probe

ABSTRACT Efavirenz induces and inhibits multiple drug‐metabolizing enzymes, contributing to significant drug–drug interactions. This study quantified the impact of multiple doses of efavirenz on CYP3A activity via midazolam metabolism using a population pharmacokinetic approach. Healthy volunteers received 1 mg midazolam orally in two sessions: first with a single 600 mg efavirenz dose and then after chronic efavirenz dosing (600 mg/day for 17 days). Midazolam and 1′‐hydroxymidazolam were quantified via LC–MS/MS, and CYP2B6, CYP3A4, and CYP3A5 genotypes were assessed using TaqMan assays. Seventy‐two volunteers ( n = 72) completed sampling after the initial dose, and 58 completed both occasions. Non‐linear mixed effects modeling was performed using the stochastic approximation expectation maximization estimation method in NONMEM. The base pharmacokinetic model employed was a two‐compartment model with first‐order absorption and first‐order elimination, incorporating proportional error terms for midazolam and 1′‐hydroxymidazolam. Covariate analysis utilized a full model approach to assess the impact of CYP3A4 and CYP3A5 genotypes, self‐reported sex, and multiple doses of efavirenz as covariates affecting the formation clearance of 1‐OH midazolam. CYP3A5 expressors exhibited a 1.27‐fold increase in midazolam clearance compared to non‐expressors, while CYP3A4 intermediate metabolizers showed a 0.94‐fold decrease relative to normal metabolizers. Clearance was also 1.30‐fold higher in females compared to males. Multiple doses of efavirenz increased midazolam clearance by 1.92‐fold (95% CI 1.65–2.28) after accounting for inter‐individual variability caused by other covariates. Furthermore, K a and bioavailability ( F ) increased with repeated efavirenz exposure. In conclusion, this population pharmacokinetic analysis effectively quantified the specific induction effect of multiple doses of efavirenz on CYP3A compared to a single dose of efavirenz. Trial Registration: ClinicalTrials.gov identifier: NCT00668395