Abstract 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 patients with MDR‐TB using the approved dose regimen. Data from 429 patients with MDR‐TB from two phase IIb studies were analyzed via nonlinear mixed‐effects modeling. Individual model‐predicted concentrations and summary PK metrics were evaluated, respectively, in the QTcF interval and transaminase level 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 a critical QTcF interval increase. No exposure–safety relationship could be described with transaminase levels despite previous reports of higher levels in patients treated with BDQ. The developed longitudinal models characterized the role of M2 concentrations in QTc interval prolongation and found no concentration dependency for transaminase level 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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