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

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.

Derivation of a Human In Vivo Benchmark Dose for Bisphenol A from ToxCast In Vitro Concentration Response Data Using a Computational Workflow for Probabilistic Quantitative In Vitro to In Vivo Extrapolation

“…This activity is known as quantitative in vitro to in vivo extrapolation (QIVIVE) (Yoon et al, 2012;Bale et al, 2014;Yoon et al, 2015). Examples of QIVIVE increasingly involve the application of physiologicallybased kinetic (PBK) modelling-based reverse dosimetry for the translation of in vitro to in vivo responses and the derivation of in vivo BMDs (Louisse et al, 2010;Louisse et al, 2012;Strikwold et al, 2013;Louisse et al, 2016;Boonpawa et al, 2017aBoonpawa et al, , 2017bLi et al, 2017;Punt et al, 2017;Strikwold et al, 2017;Adam et al, 2019;Zhao et al, 2019;Shi et al, 2020;Zhang et al, 2020). In these studies, all parameters, other than input dose or exposure, are held fixed at central values.…”

Physiologically based kinetic modelling based prediction of in vivo rat and human acetylcholinesterase (AChE) inhibition upon exposure to diazinon

“…To overcome this issue, alternative testing strategies can be considered, including physiologically based kinetic (PBK) modelling-facilitated reverse dosimetry (Louisse et al 2017 ) that enables quantitative in vitro to in vivo extrapolation (QIVIVE), as a potential novel approach in risk assessment. The PBK modelling-based alternative approach has been successfully used to predict chlorpyrifos-related AChE inhibition (Timchalk et al 2002 ; Zhao et al 2019 ) and also a variety of other chemical-induced adverse effects including for example cardiotoxicity induced by methadone, liver toxicity induced by pyrrolizidine alkaloids and developmental toxicity of retinoids, glycolethers and phenols (Boonpawa et al 2017 ; Louisse et al 2010 ; Ning et al 2019 ; Shi et al 2020 ; Strikwold et al 2013 , 2017 ). In case of DZN, previously a physiologically based pharmacokinetic and pharmacodynamic model was developed for both human and rat (Poet et al 2004 ).…”

Inter-individual variation in chlorpyrifos toxicokinetics characterized by physiologically based kinetic (PBK) and Monte Carlo simulation comparing human liver microsome and Supersome™ cytochromes P450 (CYP)-specific kinetic data as model input

“…To this end, in vitro effective concentrations of CPO were set equal to the in vivo free blood C max values of CPO in the PBK model according to the following Eq. 11 (Shi et al 2020 ): …”