Exposure-QTc modeling of bedaquiline, pretomanid, and clofazimine in adults with tuberculosis

Drug resistance (DR) poses a critical challenge to global efforts to manage tuberculosis (TB). Limited information is available on the combined cardiotoxicity of bedaquiline (BDQ), pretomanid (Pa), and clofazimine (CFZ), key drugs in current DR-TB treatment regimens. All of those prolong the QT interval. We aimed to describe this interaction to predict possible toxicities with established and novel dosing regimens to identify patients at higher risk of QT prolongation. The data for this analysis were obtained from an early-bactericidal activity study in drug-susceptible-TB of several TB drugs. We developed a competitive interaction model to evaluate combined concentration-QTc effect of all three drugs. The model was developed using ECG-matched PK measurements (105 patients, 2,062 observations). The model identified a maximum QT increase by all three drugs of 44.5 ms with respective EC50 values for BDQ, Pa, and CFZ of 0.57, 0.903, and 26.9 mg/L. For patients aged 70 years with non-black ancestry, at risk of increased BDQ exposure, simulations showed that 39.1% had a drug-induced QT change >30 ms after the loading period; this was 29.4% for following BDQ 400 mg daily regimen (part of UNITE4TB program). Reassuringly, no simulations resulted in a QTcF >500 ms, and less than 1% exceeded 480 ms or a change from baseline of >60 ms. We present a joint concentration-QT model of BDQ, Pa, and CFZ. The competitive interaction model serves as a tool to predict possible combined exposure-induced QT prolongation of these drugs in different dosing regimen and identify patients at high risk of significant QT-prolongation.