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

Citation: Svensson EM, Aweeka F, Park JG, Marzan F, Dooley KE, Karlsson MO. Model-based estimates of the effects of efavirenz on bedaquiline pharmacokinetics and suggested dose adjustments for patients coinfected with HIV and tuberculosis. Antimicrob Agents Chemother. 2013 Jun;57(6):2780-7. doi: 10.1128/AAC.00191-13. Epub 2013 Apr 9. PMID: 23571542

Access full article:

https://www.ncbi.nlm.nih.gov/pubmed/23571542

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.

Categories

CRS
Topics

Clinical Trials

P1070, Dose-Finding and Pharmacogenetic Study of Efavirenz...

Efavirenz (EFV) is an anti-HIV medicine that is commonly used to treat HIV infection in adults and children older than 3 years...

Read More

Identification of Biomarkers That Can Predict Progression...

Purpose: The C-TRIUMPH study has identified 20 household contacts (HHC), who have progressed to active TB from its HHCs cohort...

Read More

The Pharmacokinetics, Safety and Acceptability of New...

PK, safety and acceptability data and practical guidance on the optimal dosing of new more child-friendly formulations of...

Read More

P1077FF: Formula Feeding Version of the PROMISE Study...

1077FF is a randomized strategy trial, which is part of the PROMISE studies (1077BF, 1077FF, P1084s, and 1077HS). The Promoting...

Read More

A5273: Multicenter Study of Options for Second-Line...

The study is being done with people who are taking their first anti-HIV drug regimen (including an Non-Nucleoside Reverse...

Read More