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

Kelly E Dooley, Jeong-Gun Park, Susan Swindells, Reena Allen, David W Haas, Yoninah Cramer, Francesca Aweeka, Ilene Wiggins, Amita Gupta, Patricia Lizak, Sonia Qasba, Rolf van Heeswijk, Charles Flexner, ACTG 5267 Study Team, Deborah Sutherland, Marcia Free, Miriam Chicurel, Charles W Tedder, Susan L Koletar, Heather Harber, Annie Luetkemeyer, Jay Dwyer, Judith Hackman, Andrea Weiss, Kelly E Dooley, Jeong-Gun Park, Susan Swindells, Reena Allen, David W Haas, Yoninah Cramer, Francesca Aweeka, Ilene Wiggins, Amita Gupta, Patricia Lizak, Sonia Qasba, Rolf van Heeswijk, Charles Flexner, ACTG 5267 Study Team, Deborah Sutherland, Marcia Free, Miriam Chicurel, Charles W Tedder, Susan L Koletar, Heather Harber, Annie Luetkemeyer, Jay Dwyer, Judith Hackman, Andrea Weiss

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.

Conflict of interest statement

No other conflicts of interest exist

Figures

Figure 1
Figure 1
Schematic of the dosing regimen and pharmacokinetic sample collection.
Figure 2
Figure 2
Mean bedaquiline (A) and M2 (B) plasma concentration versus time curve after single dose of bedaquiline dosed at 400 mg alone (solid line) and single dose bedaquiline given together with steady state efavirenz (dashed line). Values shown represent means with standard error.
Figure 3
Figure 3
Mean (SE) efavirenz plasma concentrations versus time curves, stratified by CYP2B6 metabolizer genotype.

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