Journal
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
Volume 65, Issue 7, Pages -Publisher
AMER SOC MICROBIOLOGY
DOI: 10.1128/AAC.02687-20
Keywords
Monte Carlo simulation; multidrug resistance; pharmacodynamics; population pharmacokinetics; tuberculosis
Categories
Funding
- National Research Foundation [109056]
- Swedish Foundation for International Cooperation in Research and Higher Education (STINT)
- South African National Research Council
- National Research Foundation (NRF) [101575]
- Wellcome Trust [098316, 203135/Z/16/Z]
- South African Research Chairs Initiative of the Department of Science and Technology and National Research Foundation (NRF) of South Africa [64787]
- NRF incentive funding [UID: 85858]
- South African Medical Research Council through its TB and HIV Collaborating Centers Program
- National Department of Health [SAMRC-RFA-CC: TB/HIV/AIDS-01-2014]
- TB Alliance (Global Alliance for TB Drug Development)
- Bill and Melinda Gates Foundation
- U.S. Agency for International Development
- UK Department for International Development
- Australia Department of Foreign Affairs and Trade
- Irish Aid
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Clofazimine, a WHO group B drug for rifampin-resistant tuberculosis, can cause QT prolongation. However, using 200mg and 300mg doses of clofazimine does not significantly increase the risk of QT prolongation compared to standard treatment.
Clofazimine is classified as a WHO group B drug for the treatment of rifampin-resistant tuberculosis. QT prolongation, which is associated with fatal cardiac arrhythmias, is caused by several antitubercular drugs, including clofazimine, but there are no data quantifying the effect of clofazimine concentration on QT prolongation. Our objective was to describe the effect of clofazimine exposure on QT prolongation. Fifteen adults drug-susceptible tuberculosis patients received clofazimine monotherapy as 300mg daily for 3 days, followed by 100mg daily in one arm of a 2-week, multiarm early bactericidal activity trial in South Africa. Pretreatment Fridericia-corrected QT (QTcF) (105 patients, 524 electrocardiograms [ECGs]) and QTcFs from the clofazimine monotherapy arm matched with clofazimine plasma concentrations (199 ECGs) were interpreted with a nonlinear mixed-effects model. Clofazimine was associated with significant QT prolongation described by a maximum effect (Emax) function. We predicted clofazimine exposures using 100-mg daily doses and 2 weeks of loading with 200 and 300mg daily, respectively. The expected proportions of patients with QTcF change from baseline above 30 ms (DQTcF. 30) were 2.52%, 11.6%, and 23.0% for 100-, 200-, and 300-mg daily doses, respectively. At steady state, the expected proportion with Delta QTcF of >30 ms was 23.7% and with absolute QTcF of >450 ms was 3.42% for all simulated regimens. The use of loading doses of 200 and 300mg is not predicted to expose patients to an increased risk of QT prolongation, compared with the current standard treatment, and is, therefore, an alternative option for more quickly achieving therapeutic concentrations.
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