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Home / The International Journal of Tuberculosis and Lung Disease, Volume 26, Number 8

Altered drug exposures of first-line TB drugs in a moxifloxacin-containing treatment regimen

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BACKGROUND: Pharmacokinetic variability arising from drug-drug interactions and pharmacogenetics may influence the effectiveness of treatment regimens for TB. The Improving Treatment Success Trial compared the WHO-recommended standard treatment in TB patients with an experimental regimen substituting ethambutol with moxifloxacin (MFX) in Durban, South Africa.

METHODS: Non-linear mixed-effects modelling was used to investigate the population pharmacokinetics of rifampicin (RIF), isoniazid (INH) and pyrazinamide (PZA). A total of 25 single-nucleotide polymorphisms, including pregnane-X-receptor, were selected for analysis.

RESULTS: TB drug concentrations were available in a subset of 101 patients: 58 in the MFX arm and 43 in the control arm. Baseline characteristics were well-balanced between study arms: median age and weight were respectively 36 years and 57.7 kg; 75.2% of the patients were living with HIV. Although weight-based drug dosing was the same in the two arms, we found that RIF exposure was increased by 19.3%, INH decreased by 19% and PZA decreased by 19.2% when administered as part of the MFX-containing regimen. Genetic variation in pregnane-X-receptor (rs2472677) was associated with a 25.3% reduction in RIF exposure.

CONCLUSION: Optimised weight-based TB treatment dosing is essential when RIF, INH and PZA are co-administered with fluoroquinolones. The reduction in RIF exposure associated with pharmacogenetic variation is worrying.

Keywords: NONMEM; drug-drug interaction; pharmacogenetics; pharmacokinetics

Document Type: Research Article

Affiliations: 1: Centre for the AIDS Programme of Research in South Africa, Nelson R Mandela School of Medicine, College of Health Sciences, University of KwaZulu-Natal, Durban, South Africa, South African Medical Research Council-Centre for the AIDS Programme of Research in South Africa HIV-TB Pathogenesis and Treatment Research Unit, Doris Duke Medical Research Institute, University of KwaZulu-Natal, Durban, South Africa 2: Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa 3: Centre for the AIDS Programme of Research in South Africa, Nelson R Mandela School of Medicine, College of Health Sciences, University of KwaZulu-Natal, Durban, South Africa, South African Medical Research Council-Centre for the AIDS Programme of Research in South Africa HIV-TB Pathogenesis and Treatment Research Unit, Doris Duke Medical Research Institute, University of KwaZulu-Natal, Durban, South Africa

Publication date: August 1, 2022

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  • The International Journal of Tuberculosis and Lung Disease (IJTLD) is for clinical research and epidemiological studies on lung health, including articles on TB, TB-HIV and respiratory diseases such as COVID-19, asthma, COPD, child lung health and the hazards of tobacco and air pollution. Individuals and institutes can subscribe to the IJTLD online or in print – simply email us at [email protected] for details.

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