CYP2B6 genotype-directed dosing is required for optimal efavirenz exposure in children 3-36 months with HIV infection

Academic Article

Abstract

  • Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved. Objectives: To determine safety-specific, efficacy-specific and genotypic-specific dose requirements of efavirenz (EFV) in children aged 3 to less than 36 months with HIV infection. Design: IMPAACT P1070 was a 24-week prospective cohort trial of EFV (as open capsules) and two nucleoside reverse transcriptase inhibitors in children with HIV infection 3 to less than 36 months without tuberculosis (Cohort 1). Methods: CYP2B6 G516T genotype was determined, and intensive pharmacokinetics was performed at week 2. EFV dose was adjusted if outside the target area under the curve (AUC) 35-180 (μLg∗h/ml. Pharmacokinetic and CYP2B6 G516T genotype data were used to model EFV exposures based on Food and Drug Administration (FDA)-approved doses. Results: Forty-seven participants, median age 19 months, initiated the study regimen with 24 weeks median follow-up; 38 516GG/GT and 9 516TT genotypes. Initially, median EFV AUC was higher in 516TTvs. 516GG/GT (median 490 vs. 107(μg∗h/ml; P= 0.0001) with all 516TT above AUC target. Following an amendment that reduced the 516TT EFV dose by 75%, pharmacokinetic modeling predicted that 83% of participants met the AUC target (31/38 516GG/GT, 8/9 516TT). In contrast, modeling using P1070 data predicted that FDA-approved doses would produce subtherapeutic AUCs in almost one-third of participants with 516GG/GT and excessive AUCs in more than 50% with 516TT genotypes. Conclusion: CYP2B6 G516T genotype strongly influences EFV exposures in this age group. Genotype-directed dosing yields therapeutic EFV concentrations and appears to outperform other dosing approaches.
  • Authors

    Digital Object Identifier (doi)

    Author List

  • Moore CB; Capparelli EV; Samson P; Bwakura-Dangarembizi M; Jean-Philippe P; Worrell C; Heckman B; Purdue L; Spector SA; Benns A
  • Start Page

  • 1129
  • End Page

  • 1136
  • Volume

  • 31
  • Issue

  • 8