Integrating in vitro data and physiologically based kinetic modeling-facilitated reverse dosimetry to predict human cardiotoxicity of methadone

Miaoying Shi,Hans Bouwmeester,Marije Strikwold,Ivonne M C M Rietjens

doi:10.1007/s00204-020-02766-7

Abstract

Development of novel testing strategies to detect adverse human health effects is of interest to replace in vivo-based drug and chemical safety testing. The aim of the present study was to investigate whether physiologically based kinetic (PBK) modeling-facilitated conversion of in vitro toxicity data is an adequate approach to predict in vivo cardiotoxicity in humans. To enable evaluation of predictions made, methadone was selected as the model compound, being a compound for which data on both kinetics and cardiotoxicity in humans are available. A PBK model for methadone in humans was developed and evaluated against available kinetic data presenting an adequate match. Use of the developed PBK model to convert concentration–response curves for the effect of methadone on human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) in the so-called multi electrode array (MEA) assay resulted in predictions for in vivo dose–response curves for methadone-induced cardiotoxicity that matched the available in vivo data. The results also revealed differences in protein plasma binding of methadone to be a potential factor underlying variation between individuals with respect to sensitivity towards the cardiotoxic effects of methadone. The present study provides a proof-of-principle of using PBK modeling-based reverse dosimetry of in vitro data for the prediction of cardiotoxicity in humans, providing a novel testing strategy in cardiac safety studies.

Highlights

Traditional approaches for the risk and safety assessment of compounds rely heavily on toxicity data derived from laboratory animals, which are gradually being recognized as inappropriate models for the prediction of human health effects due to toxicodynamic and toxicokinetic differences between animals and human (Ewart et al 2014; Pang et al 2019)
The change in FPDc in the in vitro obtained field potential waveforms can be considered a surrogate endpoint for the QTc interval in the human ECG (Zwartsen et al 2019), the parameter known to be indicative for methadone-induced cardiotoxicity (Mujtaba et al 2013)
The results show that methadone induced a concentration-dependent prolongation of FPDc which is in line with the study of Kuryshev et al (2010) reporting that methadone prolonged the action potential duration using patch clamp recordings in human cardiomyocytes

Summary

Introduction

Traditional approaches for the risk and safety assessment of compounds rely heavily on toxicity data derived from laboratory animals, which are gradually being recognized as inappropriate models for the prediction of human health effects due to toxicodynamic and toxicokinetic differences between animals and human (Ewart et al 2014; Pang et al 2019). This consideration as well as the fact that animalbased testing strategies are cost and labor intensive, while increasingly considered unethical, has stimulated the development of novel testing strategies, leading to a paradigm shift in toxicity testing (Judson et al 2014). To further explore the potential applicability of this in vitro–in silico approach, the aim of the present study was to investigate whether the PBK modeling-based reverse dosimetry can be extended to predict in vivo cardiotoxicity in human, thereby providing a novel testing strategy for cardiac safety testing

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Conclusion