Safety, Tolerability, and Pharmacokinetic Interactions of... : JAIDS Journal of Acquired Immune Deficiency Syndromes (original) (raw)

Clinical Science

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

AIDS Clinical Trials Group Study A5267

Dooley, Kelly E. MD, PhD*; Park, Jeong-Gun PhD†; Swindells, Susan MBBS‡; Allen, Reena MA§; Haas, David W. MD¶; Cramer, Yoninah MS†; Aweeka, Francesca PharmD#; Wiggins, Ilene RN*; Gupta, Amita MD*; Lizak, Patricia BS#; Qasba, Sonia MD, MPH††; van Heeswijk, Rolf PharmD, PhD**; Flexner, Charles MD* the ACTG 5267 Study Team

*Johns Hopkins University School of Medicine, Baltimore, MD

†Harvard School of Public Health, Boston, MA

‡University of Nebraska Medical Center, Omaha, NE

§AIDS Clinical Trials Group Operations, Center, Silver Spring, MD

‖Division of AIDS, National Institutes of Health, Bethesda, MD

¶Vanderbilt University School of Medicine, Nashville, TN

#University of California, San Francisco, CA

**Tibotec, BVBA, Mechelen, Belgium

††Montgomery County Department of Health and Human Services, Silver Spring, MD

Dr. R.V.H. is an employee and stockholder of Johnson & Johnson. Dr. C.F. has served on scientific advisory boards for Bristol Myers Squbb and Merck, who market efavirenz in the US. All other authors have no conflicts of interest to disclose.

Supported by the AIDS Clinical Trials Group sponsored by the National Institute of Allergy and Infectious Diseases and was supported by the following grants: U01 AI068636 and AI068634, U01 AI069497 (A.G.), U01 AI069465 (A.G., C.F., I.W.) AI0699450 (S.S.), U01 AI069439, R01 AI077505 (D.W.H.), and K23AI080842 (K.E.D.). The AIDS Clinical Trials Group Human DNA Repository is supported in part by grant UL1 RR024975. Tibotec Pharmaceuticals and Bristol-Myers Squibb provided study medications.

The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Allergy and Infectious Diseases or the National Institutes of Health.

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Correspondence to: Kelly Dooley, MD, PhD, Johns Hopkins University School of Medicine, 600 North Wolfe Street, Osler 527, Baltimore, MD 21287 (e-mail: [email protected]).

Received September 19, 2011

Accepted November 8, 2011

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 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.