Bedaquiline (BDQ) has shown great value in the treatment of multidrug-resistant tuberculosis (MDR-TB) in recent years. However, exposure-safety relationships must be explored to extend the use of BDQ. Two reported safety findings for BDQ are prolongation of the QTc interval and elevation of transaminase levels. In this study, we investigated the potential relationships between BDQ and/or its main metabolite (M2) pharmacokinetic (PK) metrics and QTcF interval or transaminase levels, in MDR-TB patients using the approved dose regimen. Data from 429 MDR-TB patients from two phase IIb studies were analyzed via non-linear mixed-effects modeling. Individual model-predicted concentrations and summary PK metrics were evaluated respectively in the QTcF interval and transaminase levels exposure-response models. Investigation of further covariate effects was performed in both models. M2 concentrations were found to be responsible for the drug-related QTcF increase in a model accounting for circadian rhythm patterns, time on study, effect of concomitant medication with QT liability, and patient demographics. Simulations with the final model suggested that doses higher than the approved dose (leading to increased M2 concentrations) are not expected to lead to critical QTcF interval increase. No exposure-safety relationship could be described with transaminase levels, despite previous reports of higher levels in BDQ-treated patients. The developed longitudinal models characterized the role of M2 concentrations in QTc interval prolongation and found no concentration dependency for transaminase levels elevation, together suggesting that BDQ exposure at the high end of the observed range may not be associated with a higher risk of safety events.
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