The effect of Clofazimine Concentration on QT prolongation in patients treated for tuberculosis.

RationaleClofazimine is classified as a WHO group B drug for the treatment of rifampicin-resistant tuberculosis. QT prolongation, which is associated with fatal cardiac arrhythmias, is caused by several anti-tubercular drugs, including clofazimine, but there are no data quantifying the effect of clofazimine concentration on QT prolongation.ObjectivesTo describe the effect of clofazimine exposure on QT prolongationMethodsFifteen adults drug-susceptible tuberculosis patients received clofazimine mono-therapy as 300 mg daily for three days followed by 100 mg daily in one arm of a 2-week, multi-arm early bactericidal activity trial in South Africa. Pre-treatment Fridericia-corrected QT (QTcF) (105 patients, 524 ECGs) and QTcF's from the clofazimine-monotherapy arm matched with clofazimine plasma concentrations (199 ECGs) were interpreted with a nonlinear mixed-effects model.Measurements and Main ResultsClofazimine was associated with significant QT prolongation described by an Emax function. We predicted clofazimine exposures using 100-mg daily doses and two-weeks 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>30 ms was 23.7% and for absolute QTcF>450 ms was 3.42% for all simulated regimens.ConclusionsThe use of loading doses of 200 and 300 mg is not predicted to expose patients to increased risk of QT prolongation, compared to the current standard treatment, and is, therefore, an alternative option to achieve therapeutic concentrations faster.