| Autor: |
Abdelwahab MT; Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa., Court R; Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa., Everitt D; Global Alliance for TB Drug Development, New York, New York, USA., Diacon AH; Department of Medicine, Stellenbosch University, Tygerberg, South Africa.; Task Applied Science, Bellville, South Africa., Dawson R; Division of Pulmonology and Department of Medicine, University of Cape Town Lung Institute, Mowbray, Cape Town, South Africa., Svensson EM; Department of Pharmacy, Radboud Institute of Health Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.; Department of Pharmacy, Uppsala University, Uppsala, Sweden., Maartens G; Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa.; Wellcome Centre for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa., Denti P; Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa. |
| Abstrakt: |
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 300 mg daily for 3 days, followed by 100 mg 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 ( E max ) function. We predicted clofazimine exposures using 100-mg daily doses and 2 weeks of loading with 200 and 300 mg daily, respectively. The expected proportions of patients with QTcF change from baseline above 30 ms (ΔQTcF > 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 ΔQTcF 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 300 mg 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. |
