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

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

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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.

Original languageEnglish
Pages (from-to)2809-2827
JournalArchives of Toxicology
Volume94
DOIs
Publication statusPublished - 4 May 2020

Keywords

  • Cardiac electrophysiology
  • Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM)
  • Methadone
  • Physiologically based kinetic (PBK) modeling
  • Quantitative in vitro to in vivo extrapolation (QIVIVE)
  • Reverse dosimetry

Fingerprint Dive into the research topics of 'Integrating in vitro data and physiologically based kinetic modeling-facilitated reverse dosimetry to predict human cardiotoxicity of methadone'. Together they form a unique fingerprint.

  • Cite this