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

Research output: Contribution to journalArticle

46 Citations (Scopus)

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 (AUC 0-336 h) and 1.00 (90% CI: 0.88 to 1.13) for the maximum concentration (C max). For N-monodesmethyl metabolite, the geometric mean of ratios was 1.07 (90% CI: 0.97 to 1.19) for AUC 0-336 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.

Original languageEnglish (US)
Pages (from-to)455-462
Number of pages8
JournalJournal of Acquired Immune Deficiency Syndromes
Volume59
Issue number5
DOIs
StatePublished - Apr 15 2012

Fingerprint

efavirenz
bedaquiline
Healthy Volunteers
Acquired Immunodeficiency Syndrome
Pharmacokinetics
Clinical Trials
Safety
Confidence Intervals
Drug Interactions
Area Under Curve
Genotype
Pharmaceutical Preparations
Cytochrome P-450 CYP3A
Investigational Therapies

Keywords

  • Bedaquiline
  • CYP3A
  • Efavirenz
  • HIV
  • Pharmacokinetics
  • TMC207
  • Tuberculosis

ASJC Scopus subject areas

  • Infectious Diseases
  • Pharmacology (medical)

Cite this

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.; Park, Jeong Gun; Swindells, Susan; Allen, Reena; Haas, David W.; Cramer, Yoninah; Aweeka, Francesca; Wiggins, Ilene; Gupta, Amita; Lizak, Patricia; Qasba, Sonia; Van Heeswijk, Rolf; Flexner, Charles.

In: Journal of Acquired Immune Deficiency Syndromes, Vol. 59, No. 5, 15.04.2012, p. 455-462.

Research output: Contribution to journalArticle

Dooley, Kelly E. ; Park, Jeong Gun ; Swindells, Susan ; Allen, Reena ; Haas, David W. ; Cramer, Yoninah ; Aweeka, Francesca ; Wiggins, Ilene ; Gupta, Amita ; Lizak, Patricia ; Qasba, Sonia ; Van Heeswijk, Rolf ; Flexner, Charles. / Safety, tolerability, and pharmacokinetic interactions of the antituberculous agent TMC207 (Bedaquiline) with efavirenz in healthy volunteers : AIDS clinical trials group study A5267. In: Journal of Acquired Immune Deficiency Syndromes. 2012 ; Vol. 59, No. 5. pp. 455-462.
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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 (AUC 0-336 h) and 1.00 (90{\%} CI: 0.88 to 1.13) for the maximum concentration (C max). For N-monodesmethyl metabolite, the geometric mean of ratios was 1.07 (90{\%} CI: 0.97 to 1.19) for AUC 0-336 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.",
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T2 - AIDS clinical trials group study A5267

AU - Dooley, Kelly E.

AU - Park, Jeong Gun

AU - Swindells, Susan

AU - Allen, Reena

AU - Haas, David W.

AU - Cramer, Yoninah

AU - Aweeka, Francesca

AU - Wiggins, Ilene

AU - Gupta, Amita

AU - Lizak, Patricia

AU - Qasba, Sonia

AU - Van Heeswijk, Rolf

AU - Flexner, Charles

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N2 - 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 (AUC 0-336 h) and 1.00 (90% CI: 0.88 to 1.13) for the maximum concentration (C max). For N-monodesmethyl metabolite, the geometric mean of ratios was 1.07 (90% CI: 0.97 to 1.19) for AUC 0-336 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.

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KW - Bedaquiline

KW - CYP3A

KW - Efavirenz

KW - HIV

KW - Pharmacokinetics

KW - TMC207

KW - Tuberculosis

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