Model-based estimates of the effects of efavirenz on bedaquiline pharmacokinetics and suggested dose adjustments for patients coinfected with HIV and tuberculosis.

TitleModel-based estimates of the effects of efavirenz on bedaquiline pharmacokinetics and suggested dose adjustments for patients coinfected with HIV and tuberculosis.
Publication TypeJournal Article
Year of Publication2013
AuthorsSvensson EM, Aweeka F, Park J-G, Marzan F, Dooley KE, Karlsson MO
JournalAntimicrob Agents Chemother
Volume57
Issue6
Pagination2780-7
Date Published2013 Jun
ISSN1098-6596
KeywordsAdolescent, Adult, Aged, Anti-HIV Agents, Antitubercular Agents, Benzoxazines, Diarylquinolines, Dose-Response Relationship, Drug, Drug Interactions, Drug Therapy, Combination, HIV Infections, Humans, Middle Aged, Models, Biological, Quinolines, Stochastic Processes, Treatment Outcome, Tuberculosis, Young Adult
Abstract

Safe, effective concomitant treatment regimens for tuberculosis (TB) and HIV infection are urgently needed. Bedaquiline (BDQ) is a promising new anti-TB drug, and efavirenz (EFV) is a commonly used antiretroviral. Due to EFV's induction of cytochrome P450 3A4, the metabolic enzyme responsible for BDQ biotransformation, the drugs are expected to interact. Based on data from a phase I, single-dose pharmacokinetic study, a nonlinear mixed-effects model characterizing BDQ pharmacokinetics and interaction with multiple-dose EFV was developed. BDQ pharmacokinetics were best described by a 3-compartment disposition model with absorption through a dynamic transit compartment model. Metabolites M2 and M3 were described by 2-compartment models with clearance of BDQ and M2, respectively, as input. Impact of induction was described as an instantaneous change in clearance 1 week after initialization of EFV treatment and estimated for all compounds. The model predicts average steady-state concentrations of BDQ and M2 to be reduced by 52% (relative standard error [RSE], 3.7%) with chronic coadministration. A range of models with alternative structural assumptions regarding onset of induction effect and fraction metabolized resulted in similar estimates of the typical reduction and did not offer a markedly better fit to data. Simulations to investigate alternative regimens mitigating the estimated interaction effect were performed. The results suggest that simple adjustments of the standard regimen during EFV coadministration can prevent reduced exposure to BDQ without increasing exposures to M2. However, exposure to M3 would increase. Evaluation in clinical trials of adjusted regimens is necessary to ensure appropriate dosing for HIV-infected TB patients on an EFV-based regimen.

DOI10.1128/AAC.00191-13
Alternate JournalAntimicrob. Agents Chemother.
PubMed ID23571542
PubMed Central IDPMC3716161
Grant ListAI068634 / AI / NIAID NIH HHS / United States
AI068636 / AI / NIAID NIH HHS / United States
K23AI080842 / AI / NIAID NIH HHS / United States
P30 AI027763 / AI / NIAID NIH HHS / United States
U01 AI068634 / AI / NIAID NIH HHS / United States
U01 AI068636 / AI / NIAID NIH HHS / United States
UM1 AI068636 / AI / NIAID NIH HHS / United States
UM1 AI069496 / AI / NIAID NIH HHS / United States