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

TitleSafety, tolerability, and pharmacokinetic interactions of the antituberculous agent TMC207 (bedaquiline) with efavirenz in healthy volunteers: AIDS Clinical Trials Group Study A5267.
Publication TypeJournal Article
Year of Publication2012
AuthorsDooley KE, Park J-G, Swindells S, Allen R, Haas DW, Cramer Y, Aweeka F, Wiggins I, Gupta A, Lizak P, Qasba S, van Heeswijk R, Flexner C
Corporate AuthorsACTG 5267 Study Team
JournalJ Acquir Immune Defic Syndr
Volume59
Issue5
Pagination455-62
Date Published2012 Apr 15
ISSN1944-7884
KeywordsAdult, Anti-HIV Agents, Antitubercular Agents, Benzoxazines, Diarylquinolines, Drug Interactions, Female, HIV Infections, Humans, Male, Middle Aged, Quinolines, Young Adult
Abstract

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.

DOI10.1097/QAI.0b013e3182410503
Alternate JournalJ. Acquir. Immune Defic. Syndr.
PubMed ID22126739
PubMed Central IDPMC3302922
Grant ListAI068634 / AI / NIAID NIH HHS / United States
AI0699450 / AI / NIAID NIH HHS / United States
K23 AI080842 / AI / NIAID NIH HHS / United States
K23 AI080842-03 / AI / NIAID NIH HHS / United States
K23AI080842 / AI / NIAID NIH HHS / United States
KL2 RR024977 / RR / NCRR NIH HHS / United States
P30 AI027763 / AI / NIAID NIH HHS / United States
R01 AI077505 / AI / NIAID NIH HHS / United States
TL1 RR024978 / RR / NCRR NIH HHS / United States
U01 AI068636 / AI / NIAID NIH HHS / United States
U01 AI069439 / AI / NIAID NIH HHS / United States
U01 AI069465 / AI / NIAID NIH HHS / United States
U01 AI069497 / AI / NIAID NIH HHS / United States
UL1 RR024975 / RR / NCRR NIH HHS / United States
UL1 RR024975 / RR / NCRR NIH HHS / United States