Safety, Tolerability, and Pharmacokinetic Interactions of the Antituberculous Agent TMC207 (Bedaquiline) With Efavirenz in Healthy Volunteers

Abstract

Background Drug-drug interactions complicate management of co-infection 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 I 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 (M2) 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 ratios (GMR) for bedaquiline with efavirenz versus bedaquiline alone were 0.82 (90% CI 0.75 to 0.89) for the 14-day area under the concentration-time curve (AUC0-336h) and 1.00 (90% CI 0.88 to 1.13) for the maximum concentration (Cmax). For M2, the GMR was 1.07 (90% CI 0.97 to 1.19) for AUC0-336h and 1.89 (90% CI 1.66 to 2.15) for Cmax. 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.

Model-Based Estimates of the Effects of Efavirenz on Bedaquiline Pharmacokinetics and Suggested Dose Adjustments for Patients Coinfected with HIV and Tuberculosis

“…Study participants were healthy adults 18 to 65 years of age recruited at four ACTG sites in the United States. Subjects included had no clinical evidence of TB, negative HIV antibody test results, normal values on standard blood tests, and normal corrected QT intervals, as previously described (19). Women of reproductive potential were excluded.…”

“…Concentrations of BDQ and M2 were determined and reported previously (19). For this analysis, M3 concentrations were measured using selected stored plasma samples from the original study (8 per PK profile: predose,3,6,24,72,168,264, and 336 h).…”

“…For this analysis, M3 concentrations were measured using selected stored plasma samples from the original study (8 per PK profile: predose,3,6,24,72,168,264, and 336 h). Concentrations of BDQ and M2 in plasma were previously determined using a validated high-performance liquid chromatography method with tandem mass spectroscopy detection (19). The interassay precision (% coefficient of variation [CV]) was below 15%, and the deviation (% relative error [RE]) was within the interval of Ϫ10% and 10% for both compounds.…”

“…EFV is also an inducer of CYP3A4 activity (16) and would be predicted to reduce BDQ concentrations. In a phase I study sponsored by the AIDS Clinical Trials Group (ACTG; study A5267), 600 mg EFV once nightly reduced exposures (area under the concentration-time curve up to day 14 after dose [AUC 0 -168 ]) of single-dose BDQ by 18% (90% confidence interval [CI], 11 to 25%) and increased the maximum concentration (C max ) of M2 by 89% (90% CI, 66 to 115%) (19). However, because of the long terminal half-life of BDQ, the effects of EFV on steady-state BDQ and M2 concentrations could not be predicted using noncompartmental analyses.…”

Novel drugs against tuberculosis: a clinician's perspective

“…In one study bedaquiline given with efavirenz, which is a CYP3A4 inducer [82], led to only a slight decrease in bedaquiline concentrations [83]. In contrast a nonlinear-mixed effects model evaluating the interaction between bedaquiline and efavirenz predicted that simultaneous treatment would lead to a 52% reduction in steady state concentrations of both bedaquiline and its metabolite.…”