Dataset Information

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.

SUBMITTER: Dooley KE

PROVIDER: S-EPMC3302922 | biostudies-literature | 2012 Apr

REPOSITORIES: biostudies-literature

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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 KE Park Jeong-Gun JG Swindells Susan S Allen Reena R Haas David W DW Cramer Yoninah Y Aweeka Francesca F Wiggins Ilene I Gupta Amita A Lizak Patricia P Qasba Sonia S van Heeswijk Rolf R Flexner Charles C

Journal of acquired immune deficiency syndromes (1999) 20120401 5

<h4>Background</h4>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.<h4>Methods</h4>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 concomitan ...[more]

PMID: 22126739

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Project description:Background:External nasal dilator strips are used as nonpharmacological therapy to reduce snoring and daytime sleepiness. In a product improvement initiative, a marketed strip (BRNS) and 2 prototype nasal strips were evaluated. Objective:To compare the nasal patency and multiple-use dermal tolerability of the BRNS and prototype nasal strips using both objective and subject-reported outcome measures. Methods:Two studies were conducted separately in healthy volunteers ?18 years of age. A single-day nasal patency randomized crossover study assessed minimal cross-sectional area (MCA; second restriction) and nasal volume (using acoustic rhinometry); nasal inspiratory flow and resistance (using posterior rhinomanometry); and subject-reported evaluations of the BRNS compared with the butterfly strip and teardrop strip prototypes. A single-center, randomized, controlled, parallel-group, evaluator-blinded study assessed dermal tolerability of the BRNS and the butterfly strip over 7 consecutive nights of use, using the Dermal Response Scale (DRS) and subject-reported comfort and ease of removal. Results:In the Patency study (N?=?50), all 3 strips demonstrated significant improvement from baseline in MCA, nasal volume, and nasal flow parameters (resistance and peak flow). The prototype strips demonstrated significantly more improvement in nasal volume than the BRNS, and the butterfly strip showed significantly more improvement in MCA than the BRNS; all strips were similar with respect to nasal flow and subject-reported nasal breathing outcomes. In the Dermal Tolerability study (N?=?82), all subjects scored 0 (no evidence of irritation) on the DRS at all 7 morning assessments; the BRNS was numerically, but not significantly, superior to the butterfly strip on subject-reported outcomes. Conclusion:The Patency study demonstrated significant improvement from baseline in nasal dimensions and flow for all 3 evaluated strips; between-strip differences were confined to nasal dimensions. Both the BRNS and butterfly strip were generally well tolerated, with no evidence of dermal response over 7 consecutive nights of use.ClinicalTrials.gov identifiers: NCT01105949 and NCT01495494.

Dataset Information

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

Publications

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

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