Bedaquiline appears to antagonize its own main metabolite’s QTcF interval prolonging effect
Lénaïg Tanneau (1), Elin M Svensson (1,2), Stefaan Rossenu (3), Mats O Karlsson (1)
(1) Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden, (2) Department of Pharmacy, Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, the Netherlands, (3) Department Global Clinical Pharmacology, Janssen Pharmaceutica NV, Beerse, Belgium
Objectives: More than 40 years after rifampicin’s discovery, bedaquiline (BDQ) was the first anti-tuberculosis drug with a novel mechanism of action that received accelerated approval by the US FDA in 2012 for the treatment of multidrug-resistant (MDR) tuberculosis (TB) in adults as part of combination therapy [1]. It has been shown that BDQ shortens the time to sputum culture conversion and increases the cure rate [2]. On the other hand, administration of BDQ may lead to prolongation of the heart’s QT interval, which is a safety concern since patients can develop cardiac arrhythmias such as Torsades de Pointes (risk factor of sudden death) [3].
The objective of this study was to investigate potential relationships between concentrations of BDQ and/or its main metabolite (M2) and QTcF interval (QT interval corrected with Fridericia’s coefficient) in MDR TB patients using the approved BDQ dose regimen.
Methods: Data were obtained from two phase IIb studies (C208 [3] and C209 [4]) and were pooled to include a total of 335 patients treated with BDQ and 105 patients with placebo. Patients were newly diagnosed (all C208 patients and 10% of C209 patients) or treatment-experienced subjects and received BDQ (200mg qd for 2 two weeks, then 400mg tiw) or placebo for 24 weeks (or 8 weeks in stage 1 of C208) in combination with a background regimen of 5-7 anti-TB drugs. Pre-dose BDQ/M2 PK samples were drawn at 7 occasions in all patients of the placebo controlled C208 study and full PK profiles performed at week 2, 8 and 24 (stage 1) or week 24 (for a subset of patients in stage 2). The open-label C209 study included 3 pre-dose samples per patient (week 2, 12 and 24). Single ECGs were performed weekly while triplicate measurements at pre-dose and 5 hour post-dose were taken at week 2, 8, 12 (only C209) and 24. The trials were conducted in accordance with Good Clinical Practice standards and received ethical approval from appropriate local authorities.
Since a PK-model for BDQ and M2 was previously established for these trials [5], a sequential approach was used. The individual model-predicted BDQ and M2 concentrations were evaluated as predictors (covariates) in the development of the pharmacodynamic (PD) model for QTcF interval. The effect of the presence/absence of background regimen also was explored.
Results: 14263 observations of QTcF interval were recorded at baseline (just before start of study treatment) and during the treatment period. The baseline QTcF of 399 ms (without any TB treatment) increased by 0.8 ms in the presence of background regimen in C208 study and by 4.19 ms in C209 study. After testing separate drug effects for BDQ and M2 (on/off, linear, Emax, sigmoidal Emax), as well as full and partial competitive agonist models, the model that best described the data during the treatment period was a competitive antagonist model [6, Eq 3:49]. Thus, BDQ appears to act as an antagonist of M2 effect and has no intrinsic activity (i.e. Emax,BDQ is zero). Related parameters were estimated at 12.9 ms (RSE 5%) for Emax,M2, and at 229 ng/mL (RSE 8%) for EC50,BDQ and 14 ng/mL (RSE 6%) for EC50,M2. This model performed better than Emax effect models of BDQ and M2 alone, by 1255 and 160 points drop in OFV, respectively. In addition, analysis of each study data separately (C208 and C209) showed robustness of the results (pharmacologic mechanism and parameters estimates).
This would mean that the QT prolongation is driven exclusively by M2 concentrations while BDQ antagonizes the effect of M2 on QT prolongation. The interaction of both BDQ and M2 at the same target is supported by results from pre-clinical studies, where both inhibit IKr channel (known to cause prolonged QT) in hERG transfected kidney cells. However, the relative magnitude of each effect could not be quantified in vitro [7].
Conclusions: The QTcF interval prolongation observed in the phase IIb studies of BDQ was explained by an effect of the background regimen and M2 exposures, while BDQ antagonizes the effect of M2. A QTcF model can together with previously developed models for population PK [5] with drug-drug interactions [8–12], and sputum conversion [13], inform an integrated dose-exposure-efficacy-safety analysis of BDQ.
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