Model-Predicted Impact of ECG Monitoring Strategies During Bedaquiline Treatment

Abstract

Background The M2 metabolite of bedaquiline causes QT-interval prolongation, making ECG monitoring of patients receiving bedaquiline for drug-resistant tuberculosis necessary. The objective of this study was to determine the relationship between M2 exposure and Fridericia-corrected QT (QTcF)-interval prolongation and to explore suitable ECG monitoring strategies for six-month bedaquiline treatment. Methods Data from the PROBeX study, a prospective observational cohort study, were used to characterize the relationship between M2 exposure and QTcF. Established non-linear mixed effects models were fitted to pharmacokinetic and ECG data. In a virtual patient population, QTcF values were simulated for scenarios with and without concomitant clofazimine. ECG monitoring strategies to identify patients who need to interrupt treatment (QTcF > 500 ms) were explored. Results 170 patients were included, providing 1131 bedaquiline/M2 plasma concentrations and 1702 QTcF measurements. 2.1% of virtual patients receiving concomitant clofazimine had QTcF > 500 ms at any point during treatment (0.7% without concomitant clofazimine). With monthly monitoring, almost all patients with QTcF > 500 ms were identified by week 12; after week 12, patients were predominantly falsely identified as QTcF > 500 ms due to stochastic measurement error. Following a strategy with monitoring before treatment and at weeks 2, 4, 8 and 12 in simulations with concomitant clofazimine, 93.8% of all patients who should interrupt treatment were identified and 26.4% of all interruptions were unnecessary (92.1% and 32.2%, respectively, without concomitant clofazimine). Conclusion Our simulations enable an informed decision for a suitable ECG monitoring strategy by weighing the risk of missing patients with QTcF > 500 ms and that of interrupting bedaquiline treatment unnecessarily. We propose ECG monitoring before treatment and at weeks 2, 4, 8 and 12 after starting bedaquiline treatment.

Validation of a Handheld 6-Lead Device for QT Interval Monitoring in Resource-Limited Settings

“…Although programmatic identification of a prolonged QTc interval has never been shown to reduce mortality in a general population, developing prospective randomized evidence supporting the superiority of specific ECG monitoring strategies or QTc interval action thresholds is implausible given the rarity of torsade de pointes and the difficulty of establishing causality. 7 Nevertheless, several investigators 10 , 26 , 56 have reasonably suggested ECG monitoring schedules either more targeted or less intensive than current regulatory guidelines. Simple, handheld 6-lead devices could reduce the need to perform 12-lead ECG monitoring in resource-limited settings and extend the reach of QTc assessment when needed, resulting in more patient-centered care.…”

How much should we still worry about QTc prolongation in rifampicin-resistant tuberculosis? ECG findings from TB-PRACTECAL clinical trial

“…Interestingly, van Beek et al using PROBeX data, simulated a strategy of ECG monitoring and found that the vast majority of patients that should have interrupted bedaquiline treatment due to a QTcF interval >500 ms had already been identified by week 12 ( 20 ).…”