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Free Content Pharmacokinetic interaction between bedaquiline and clofazimine in patients with drug-resistant tuberculosis

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BACKGROUND: Bedaquiline (BDQ) and clofazimine (CFZ) are both recommended for treating drug-resistant tuberculosis (DR-TB). As CFZ is an inhibitor of the cytochrome P450 isoenzyme 3A4 (CYP3A4) in vitro, and BDQ a substrate of CYP3A4, there is a potential for pharmacokinetic (PK) drug-drug interaction that may result in increased BDQ exposure when co-administered with CFZ, which could increase the toxicity of BDQ.

METHODS: We assessed the effect of co-administered CFZ on BDQ bioavailability, or on clearance of BDQ and its N-monodesmethyl metabolite (M2), in patients with DR-TB using a population PK model developed from data of patients with DR-TB. This was a secondary analysis of a study designed to explore drug-drug interactions between BDQ and antiretrovirals.

RESULTS: Of 46 participants, 30 were on concomitant CFZ when intensive PK sampling of BDQ was done. CFZ did not have a statistically significant effect on BDQ bioavailability (−9.1%, 90%CI −22.8 to +7.1; P = 0.19) or on BDQ and M2 clearance (+12.2%, 90%CI −13.7 to +38; P = 0.32).

CONCLUSION: We did not find a statistically significant PK drug-drug interaction between BDQ and CFZ, but cannot exclude a potentially clinically relevant interaction due to the wide confidence intervals of the estimated interaction effects.
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Keywords: BDQ; CFZ; TB; drug-drug interaction; population pharmacokinetics

Document Type: Research Article

Affiliations: 1: Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, South Africa 2: Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden 3: Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden, Department of Pharmacy, Radboud Institute for Health Sciences, Radboud University Medical Centre, Nijmegen, The Netherlands

Publication date: January 1, 2018

This article was made available online on November 16, 2017 as a Fast Track article with title: "Pharmacokinetic interaction between bedaquiline and clofazimine in patients with drug-resistant tuberculosis".

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  • The International Journal of Tuberculosis and Lung Disease publishes articles on all aspects of lung health, including public health-related issues such as training programmes, cost-benefit analysis, legislation, epidemiology, intervention studies and health systems research. The IJTLD is dedicated to the continuing education of physicians and health personnel and the dissemination of information on tuberculosis and lung health world-wide.

    Certain IJTLD articles are selected for translation into French, Spanish, Chinese or Russian. They are available on the Union website

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