title: Pharmacometric characterization of efavirenz developmental pharmacokinetics and pharmacogenetics in HIV-infected children.
abstract: The aim of this analysis was to create a pharmacometric model of efavirenz developmental pharmacokinetics and pharmacogenetics in HIV-infected children. The data consisted of 3,172 plasma concentrations from 96 HIV-1-infected children who participated 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 and multidrug-resistance transporter gene (MDR1)-C3435T polymorphisms were assessed. A one-compartment model using weight-based allometry on oral clearance and apparent volume of distribution adequately described the data. A sigmoid maximum-effect (Emax) maturation model 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 demonstrated no effect.
authors.affiliation: Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota, USA.
authors.forename: Ahmed Hamed
authors.initials: AH
authors.lastname: Salem
authors.forename: Courtney V
authors.initials: CV
authors.lastname: Fletcher
authors.forename: Richard C
authors.initials: RC
authors.lastname: Brundage
mesh_terms: D000293:Adolescent; D000480:Alkynes; D019380:Anti-HIV Agents / Q000627:therapeutic use*; D048588:Benzoxazines / Q000627:therapeutic use*; D001835:Body Weight / Q000187:drug effects; D002648:Child; D002675:Child, Preschool; D003521:Cyclopropanes; D015658:HIV Infections / Q000188:drug therapy* / Q000235:genetics; D006801:Humans; D007223:Infant; D010597:Pharmacogenetics / Q000379:methods
chemical_list: D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D003521:Cyclopropanes; C098320:efavirenz