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

Citation: 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. Safety, tolerability, and pharmacokinetic interactions of the antituberculous agent TMC207 (bedaquiline) with efavirenz in healthy volunteers: AIDS Clinical Trials Group Study A5267. J Acquir Immune Defic Syndr. 2012 Apr 15;59(5):455-62. doi: 10.1097/QAI.0b013e3182410503. PMID: 22126739. PMCID: PMC3302922.

Access full article:

http://www.ncbi.nlm.nih.gov/pubmed/22126739

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

A5274: REMEMBER, Reducing Early Mortality and Early...

This study is being done in people who are starting HIV treatment and who live in areas where the TB infection rate is high. The...

Read More

P1073: Study of Immune Reconstitution Inflammatory Syndrome...

P1073 is a case controlled prospective, clinical, observational and pathogenesis study of HIV-infected infants and children...

Read More

A5361s: Pitavastatin to REduce Physical Function Impairment...

A5361s is a prospective study to determine the effects of pitavastatin on physical function. The study will enroll participants...

Read More

A5332: Randomized Trial to Prevent Vascular Events in HIV...

REPRIEVE (A5332) is a large double-blind, randomized, placebo-controlled study of pitavastatin or placebo for about 72 months....

Read More

NWCS 408: Examining Longitudinal Cytokine Profiles in HIV-TB...

Using existing data from A5274 and data obtained from retrospectively testing available biospecimens, we propose the following...

Read More