Pharmacometric Characterization of Efavirenz Developmental Pharmacokinetics

The aim of this analysis was to create a pharmacometric model of efavirenz developmental pharmacokinetics and pharmacoge-netics in HIV-infected children. The data consisted of 3,172 plasma concentrations from 96 HIV-1-infected children who partici-pated in the Pediatric AIDS Clinical Trials Group 382 (PACTG382) study. Analyses were performed using NONMEM, and the impacts of body weight, age, race, sex, formulation, liver function, and cytochrome P450 2B6 (CYP2B6)-G516T andmultidrug-resistance transporter gene (MDR1)-C3435T polymorphisms were assessed. A one-compartment model using weight-based al-lometry on oral clearance and apparent volume of distribution adequately described the data. A sigmoid maximum-effect (Emax) maturationmodel demonstrated an increase in oral clearance with age to reach 90 % of its mature level by the age of 9 months. The liquid formulation bioavailability relative to the capsule was found to increase with age to reach 90 % of its mature value by the age of 8 years. The CYP2B6-G516T polymorphism decreased oral clearance, while the MDR1-C3435T polymorphism demon-strated no effect. Efavirenz (EFV) is a potent nonnucleoside reverse transcriptaseinhibitor (NNRTI) that is indicated, in combination with other antiretroviral agents, for treatment of human immunodefi-ciency virus type 1 (HIV-1) infection (1). EFV is highly bound to plasma proteins, predominantly albumin (2). It is mainly metab-olized by cytochrome P450 enzymes to hydroxylated derivative