Exposure–safety analysis of QTc interval and transaminase levels following bedaquiline administration in patients with drug‐resistant tuberculosis

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. StudyHighlights WHATISTHECURRENTKNOWLEDGEONTHETOPIC?The following two main adverse effects have been associated with bedaquiline use: QTc prolongation and elevated transaminase levels. Previous analyses have

Assessing Prolongation of the Corrected QT Interval with Bedaquiline and Delamanid Coadministration to Predict the Cardiac Safety of Simplified Dosing Regimens

“…As a first step, the evaluation of the base model with bedaquiline arm data, using the PRIOR functionality, resulted in parameter estimates and precision in line with published results (see Table 2 and Ref. 18 ). The exploration of bedaquiline's contribution to the drug effect resulted in a nonsignificant improvement of the data fit, either as a single agent or as a combination with M2 (see Table S3).…”

“…A previously developed model describing the relation between M2 concentration and QTcF interval was used as the base model. 18 In addition to the drug effect (DE), this model included several components that influenced the QTcF interval, such as participants' characteristics (age, sex, race, electrolyte levels) on baseline QTcF, the circadian rhythm, and the effect of time on treatment (see Figure S1). No covariate search was performed on top of the base model, given that no new potential covariates were available in the analysis data set, compared with the base model.…”

Addressing bedaquiline treatment interruptions in the treatment of drug-resistant TB

“…This model also predicted doses of BDQ above the approved dose will not lead to critical QTcF interval increases. 17 We consider our simulations for BDQ (parent compound) exposure appropriate for efficacy and safety.…”

Population Pharmacokinetics of Delamanid and its Main Metabolite DM-6705 in Drug-Resistant Tuberculosis Patients Receiving Delamanid Alone or Coadministered with Bedaquiline

“…This can lead to tachyarrhythmias, such as torsade de pointe, which are a risk factor of sudden death, so are important to detect. However, this effect has not primarily been attributed to delamanid and bedaquiline themselves, but to their main metabolites, DM-6705 for delamanid and M2 for bedaquiline [8][9][10].…”