Impact of CYP2B6 genotype, tuberculosis therapy, and formulation on efavirenz pharmacokinetics in infants and children under 40 months of age

Mina Nikanjam, Lana Tran, Ellen G. Chadwick, Mutsa Bwakura-Dangarembizi, Carolyn Bolton Moore, Pearl Samson, Stephen A. Spector, Nahida Chakhtoura, Patrick Jean-Philippe, Lisa Frenkel, Bonnie Zimmer, Alex Benns, Jennifer Libous, Edmund V. Capparelli*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

Objective: Dosing efavirenz (EFV) in children less than 3 years of age is challenging due to large variability in drug levels. This study evaluated differences in pharmacokinetics with tuberculosis (TB) therapy, formulation, age, and CYP2B6 genotype. Design: Pharmacokinetic data from three IMPAACT/PACTG studies (P382, P1021, and P1070) for children initiating therapy less than 40 months of age were evaluated. Methods: Pharmacokinetic data were combined in a population pharmacokinetic model. Exposure from the 2-week pharmacokinetic visit was compared with changes in viral RNA between the Week 0 and Week 4 visits. Results: The model included 103 participants (19 on TB therapy). CYP2B6 516 genotype information was available for 82 participants (TT: 15, GT: 28, GG: 39). Median age at the first pharmacokinetic visit was 17.0 months (range: 2.0 - 39.0 months). Liquid formulation led to a 42% decrease in bioavailability compared with opened capsules. TB therapy (isoniazid and rifampin) led to a 29% decreased clearance, however Monte Carlo simulations demonstrated the majority of participants on TB therapy receiving standard EFV dosing to be in the target area under the curve range. Clearance was 5.3-fold higher for GG than TT genotype and 3.3-fold higher for GT than TT genotype. Age did not have a significant effect on clearance in the final model. Initial viral RNA decay was lower for patients in the lowest quartile of exposures (area under the curves) than for higher quartiles (P = 0.013). Conclusion: EFV dosing should account for CYP2B6 516 genotype and formulation, but does not require adjustment for concurrent TB therapy.

Original languageEnglish (US)
Pages (from-to)525-532
Number of pages8
JournalAIDS
Volume36
Issue number4
DOIs
StatePublished - Mar 15 2022

Funding

This publication resulted in part from research supported by the UC San Diego Center for Research of Pediatric and Developmental Pharmacology (RPDP) – a NICHD funded program (5U54HD090259) to E.V.C. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. Overall support for the International Maternal Pediatric Adolescent AIDS Clinical Trials Network (IMPAACT) was provided by the National Institute of Allergy and Infectious Diseases (NIAID) with co-funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) and the National Institute of Mental Health (NIMH), all components of the National Institutes of Health (NIH), under Award Numbers UM1AI068632 (IMPAACT LOC), UM1AI068616 (IMPAACT SDMC) and UM1AI106716 (IMPAACT LC), and by NICHD contract number HHSN275201800001I. Funding for this study was also provided by the Intramural Research Program of the Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health.

Keywords

  • CYP2B6
  • Efavirenz
  • Isoniazid
  • Pediatrics
  • Rifampin
  • Tuberculosis

ASJC Scopus subject areas

  • Infectious Diseases
  • Immunology and Allergy
  • Immunology

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