Safety, tolerability, and pharmacokinetic interactions of the antituberculous agent TMC207 (bedaquiline) with efavirenz in healthy volunteers: AIDS Clinical Trials Group Study A5267.

Topic:

HIV PreventionTuberculosis

Authors:

Dooley KE, Park JG, Swindells S, Allen R, Haas DW, Cramer Y, Aweeka F, Wiggins I, Gupta A, Lizak P, Qasba S, van Heeswijk R, Flexner C; ACTG 5267 Study Team.

External Link:

Link to article

BACKGROUND:

Drug-drug interactions complicate management of coinfection with HIV-1 and Mycobacterium tuberculosis. Bedaquiline (formerly TMC207), an investigational agent for the treatment of tuberculosis, is metabolized by cytochrome P450 (CYP) 3A which may be induced by the antiretroviral drug efavirenz.

METHODS:

This was a phase 1 pharmacokinetic drug interaction trial. Each healthy volunteer received two 400 mg doses of bedaquiline, the first alone and the second with concomitant steady-state efavirenz. Plasma pharmacokinetic sampling for bedaquiline and its N-monodesmethyl metabolite was performed over 14 days after each bedaquiline dose. Steady-state efavirenz pharmacokinetics were also determined. Efavirenz metabolizer status was based on CYP2B6 composite 516/983 genotype.

RESULTS:

Thirty-three of 37 enrolled subjects completed the study. Geometric mean of ratios for bedaquiline with efavirenz versus bedaquiline alone were 0.82 [90% confidence interval (CI): 0.75 to 0.89] for the 14-day area under the concentration-time curve (AUC0-336 h) and 1.00 (90% CI: 0.88 to 1.13) for the maximum concentration (Cmax). For N-monodesmethyl metabolite, the geometric mean of ratios was 1.07 (90% CI: 0.97 to 1.19) for AUC0-336 h and 1.89 (90% CI: 1.66 to 2.15) for C(max). There were no grade 3 or 4 clinical adverse events. One subject developed asymptomatic grade 3 serum transaminase elevation, prompting study drug discontinuation. Efavirenz concentrations stratified by CYP2B6 genotype were similar to historical data.

CONCLUSIONS:

Single-dose bedaquiline was well tolerated alone and with steady-state efavirenz. The effect of efavirenz on bedaquiline concentrations is unlikely to be clinically significant.

J Acquir Immune Defic Syndr. 2012 Apr 15;59(5):455-62. doi: 10.1097/QAI.0b013e3182410503. PMID: 22126739 [PubMed - indexed for MEDLINE] Free PMC Article

Categories

CRS
Topics

Clinical Trials

A5337: Safety and Efficacy of Sirolimus for HIV Reservoir...

When a person becomes infected with HIV the immune system (the system that helps fight infection) is weakened (partly because...

Read More

A5350: Effects of Visbiome Extra Strength on Gut Microbiome...

Many factors contribute to the development of aging-related conditions, including gastrointestinal (GI) diseases, such as...

Read More

A5320: Viral Hepatitis C Infection Long-term Cohort Study...

A5320/V-HICS is an observational, prospective, long-term follow-up study in hepatitis C virus (HCV) monoinfected and HCV/HIV-1...

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

HPTN 069: A Phase II Randomized, Double-Blind, Study of the...

HPTN 069 is a phase II, four-arm, multisite, randomized, double-blinded trial. To assess the safety and tolerability of four...

Read More