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

Content Provider	Europe PMC
Author	Shi, Miaoying Bouwmeester, Hans Rietjens, Ivonne M. C. M. Strikwold, Marije
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.Electronic supplementary materialThe online version of this article (10.1007/s00204-020-02766-7) contains supplementary material, which is available to authorized users.
Related Links	https://europepmc.org/backend/ptpmcrender.fcgi?accid=PMC7395048&blobtype=pdf
ISSN	03405761
Journal	Archives of Toxicology [Arch Toxicol]
Volume Number	94
DOI	10.1007/s00204-020-02766-7
PubMed Central reference number	PMC7395048
Issue Number	8
PubMed reference number	32367273
e-ISSN	14320738
Language	English
Publisher	Springer Berlin Heidelberg
Publisher Date	2020-05-04
Publisher Place	Berlin/Heidelberg
Access Restriction	Open
Rights License	Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. © The Author(s) 2020
Subject Keyword	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
Content Type	Text
Resource Type	Article
Subject	Health, Toxicology and Mutagenesis Medicine Toxicology