title: Safety, tolerability, and pharmacokinetic interactions of the antituberculous agent TMC207 (bedaquiline) with efavirenz in healthy volunteers: AIDS Clinical Trials Group Study A5267.
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.
authors: Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. kdooley1@jhmi.edu
authors: Kelly E
authors: KE
authors: Dooley
authors: Jeong-Gun
authors: JG
authors: Park
authors: Susan
authors: S
authors: Swindells
authors: Reena
authors: R
authors: Allen
authors: David W
authors: DW
authors: Haas
authors: Yoninah
authors: Y
authors: Cramer
authors: Francesca
authors: F
authors: Aweeka
authors: Ilene
authors: I
authors: Wiggins
authors: Amita
authors: A
authors: Gupta
authors: Patricia
authors: P
authors: Lizak
authors: Sonia
authors: S
authors: Qasba
authors: Rolf
authors: R
authors: van Heeswijk
authors: Charles
authors: C
authors: Flexner
mesh_terms: D000328:Adult; D000480:Alkynes; D019380:Anti-HIV Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000995:Antitubercular Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D048588:Benzoxazines / Q000493:pharmacokinetics* / Q000627:therapeutic use; D003521:Cyclopropanes; D064687:Diarylquinolines; D004347:Drug Interactions; D005260:Female; D015658:HIV Infections / Q000188:drug therapy*; D006801:Humans; D008297:Male; D008875:Middle Aged; D011804:Quinolines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: D000480:Alkynes; D019380:Anti-HIV Agents; D000995:Antitubercular Agents; D048588:Benzoxazines; D003521:Cyclopropanes; D064687:Diarylquinolines; D011804:Quinolines; C493870:bedaquiline; C098320:efavirenz