Integrating in vitro data and physiologically based kinetic modeling-facilitated reverse dosimetry to predict human card
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ORGAN TOXICITY AND MECHANISMS
Integrating in vitro data and physiologically based kinetic modeling‑facilitated reverse dosimetry to predict human cardiotoxicity of methadone Miaoying Shi1 · Hans Bouwmeester1 · Ivonne M. C. M. Rietjens1 · Marije Strikwold2 Received: 26 February 2020 / Accepted: 22 April 2020 © The Author(s) 2020
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. Keywords Cardiac electrophysiology · Methadone · Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) · Quantitative in vitro to in vivo extrapolation (QIVIVE) · Physiologically based kinetic (PBK) modeling · Reverse dosimetry Abbreviations ADME Absorption, distribution, metabolism and excretion AIC Akaike’s Information Criterion AUC Area under the curve BMD Benchmark dose
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00204-020-02766-7) contains supplementary material, which is available to authorized users. * Miaoying Shi [email protected] 1
Division of Toxicology, Wageningen University, Stippeneng 4, 6708 WE Wageningen, The Netherlands
Van Hall Larenstein University of Applied Sciences, 8901 BV Leeuwarden, The Netherlands
2
BMDL10—BMDU10 Lower and upper 95% confidence limit of BMD resulting in 10% effect BMR Benchmark response BMC20 Benchmark concentration that induced a 20% change EDDP 2-Ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine EMDP 2-Ethyl-5-methyl-3,3-diphenylpyrroline FPD Field potential duration FPDc Field potential duration corrected for beat rate hERG Human ether-à-go-go-related gene hiPSC-CM Human induced pluripotent st
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