Managing Director ESQlabs, GmbH Saterland, Niedersachsen, Germany
Disclosure(s):
Stephan Schaller, PhD: No financial relationships to disclose
Objectives: Cardiotoxicity, i.e. QTc prolongation and resulting arrythmia, is associated with some anti-tuberculosis (TB) drugs [1]. The purpose of this work is to develop an open-source framework to derisk the development and use of new drug therapies against tuberculosis (TB). It will be achieved thanks to the following objectives: (1) Develop a data-driven QTc prolongation prediction model for TB drugs, (2) Translate a mechanistic cardiac electrophysiology model in an open-source framework, (3) Predict cardiotoxicity and gender susceptibility to TB drug-induced arrhythmias [2,3] (4) Develop PBPK models of TB drugs in the Open Systems Pharmacology Suite (OSPS) [4] (5) Optimize dosing to ensure cardiac safety in populations at risk.
Methods: A data-driven QTc prolongation model was developed for Moxifloxacine, and Bedaquiline, adapted from [5]. It utilizes in vitro ion channel (hERG) binding data to predict each drug’s efficacy and proarrhythmic risk by combining a receptor binding and a transduction model to quantify how efficiently hERG block potency translates to a downstream QTc prolongation. Then, a mechanistic cardiac electrophysiology model based on the O’Hara-Rudy (ORd) model [2] was translated from MATLAB to R, its implementation validated against CiPA drugs, and applied to TB drugs using literature-derived IC50 values. Resulting drug effects on cardiomyocyte action potential and several biomarkers (e.g. AP duration at 90% repolarization ‘APD90’) were compared to literature data. Finally, PBPK models of 4 selected TB drugs were developed and made available in the latest OSPS v12.0 and integrated with the PD models for safe dose predictions.
Results: The data-driven QTc prediction model effectively reproduced the dose-QTc relationship for Moxifloxacin and Bedaquiline [6,7]. The ORd-derived model successfully simulated action potential (AP) effects of high-risk CiPA drugs in male and female virtual populations (50 patients). For instance, under 0.5 mg Dofetilide for 12h, APD90 was 405.4 ± 15.2ms, and intracellular systolic Ca2+ concentration was 1.02 ± 0.56 µM, matching the values reported in the original model [2] thereby verifying the new R implementation. Effects of TB-drugs such as Moxifloxacine were simulated using in vitro input measurements, fitting unknown IC50 and hill coefficients to align with observed data, when necessary. Additional in vitro ion current inhibition measurements for TB-drugs are necessary to improve forward predictions. PBPK models replicated dose-concentration relationships (e.g., isoniazid evaluated across 11 clinical studies in healthy and TB patients). Integration with the PD models demonstrated the framework’s capacity to optimize the dose to ensure cardiac safety in a female population.
Conclusions: PBPK models of TB drugs and QSP cardiac effect models have been implemented in an open-source framework to enhance dose testing and cardiac safety assessment. This ensures that technological advancements in anti-TB drug PK and PD are accessible to a broader audience. Our work highlights the need for systematic in vitro ion current inhibition data for TB drugs. Next steps involve further validating the framework with new in vitro data and coupling it with a model of TB progression.
Citations: [1] Monedero-Recuero I, Hernando-Marrupe L, Sánchez-Montalvá A, Cox V, Tommasi M, Furin J, et al. QTc and anti-tuberculosis drugs: a perfect storm or a tempest in a teacup? Review of evidence and a risk assessment. int j tuberc lung dis. 2018 Dec 1;22(12):1411–21 [2] James AF, Choisy SCM, Hancox JC. Recent advances in understanding sex differences in cardiac repolarization. Progress in Biophysics and Molecular Biology. 2007 Jul;94(3):265–319 [3] Llopis-Lorente J, Baroudi S, Koloskoff K, Mora MT, Basset M, Romero L, et al. Combining pharmacokinetic and electrophysiological models for early prediction of drug-induced arrhythmogenicity. Computer Methods and Programs in Biomedicine. 2023 Dec;242:107860 [4] Lippert J, Burghaus R, Edginton A, Frechen S, Karlsson M, Kovar A, et al. Open Systems Pharmacology community - an open access, open source, open science approach to modeling and simulation in pharmaceutical sciences. CPT Pharmacometrics Syst Pharmacol. 2019 Oct 31 [5] Gotta V, Yu Z, Cools F, Ammel K, Gallacher DJ, Visser SAG, et al. Application of a systems pharmacology model for translational prediction of HERG ‐mediated QT c prolongation. Pharmacol Res Perspect [Internet]. 2016 Dec [6] Taubel J, Ferber G, Lorch U, Batchvarov V, Savelieva I, Camm AJ. Thorough QT study of the effect of oral moxifloxacin on QTC interval in the fed and fasted state in healthy Japanese and Caucasian subjects. Brit J Clinical Pharma. 2014 Jan;77(1):170–9 [7] Tanneau L, Svensson EM, Rossenu S, Karlsson MO. Exposure–safety analysis of QTc interval and transaminase levels following bedaquiline administration in patients with drug‐resistant tuberculosis. CPT Pharmacom & Syst Pharma. 2021 Dec;10(12):1538–49.
Keywords: Tuberculosis drug PBPK, Cardiac electrophysiology, Quantitative Systems Pharmacology
