A new approach methodology (NAM) for the prediction of (nor)ibogaine-induced cardiotoxicity in humans.
ALTEX – January 01, 2021
Source: PubMed
Summary
Predicting drug side effects without animal testing is crucial. A new method successfully predicted human heart toxicity from anti-addiction drugs ibogaine and noribogaine. Researchers developed physiologically based kinetic (PBK) modeling, integrating data from human induced pluripotent stem cell-derived cardiomyocytes (hipsc-cm) and other lab tests. This allowed for quantitative in vitro to in vivo extrapolation (QIVIVE) using reverse dosimetry to estimate real-world cardiac safety evaluation. The predictions closely matched existing human data, offering a promising non-animal approach for assessing drug safety.
Abstract
The development of non-animal-based new approach methodologies (NAMs) for chemical risk assessment and safety evaluation is urgently needed. The aim of the present study was to investigate the applicability of an in vitro-in silico approach to predict human cardiotoxicity of the herbal alkaloid ibogaine and its metabolite noribogaine, which are promising anti-addiction drugs. Physiologically based kinetic (PBK) models were developed using in silico-derived parameters and biokinetic data obtained from in vitro liver microsomal incubations and Caco-2 transport studies. Human induced pluripotent stem cell-derived cardiomyocytes combined with a multi-electrode array (MEA) assay were used to determine in vitro concentration-dependent cardiotoxicity reflected by prolongation of field potential duration, which was subsequently translated to in vivo dose-dependent prolongation of the QTc (heart rate corrected duration from ventricular depolarization to repolarization) using PBK modeling-based reverse dosimetry. Results showed that the predictions matched well with in vivo kinetic data and QTc data for ibogaine and noribogaine available in the literature, indicating a good performance of the NAM. Benchmark dose analysis of the predicted dose response curves adequately predicted the onset of in vivo cardiotoxicity detected by QTc prolongation upon oral exposure to ibogaine and noribogaine. The present study provides an additional proof-of-principle of using PBK modeling-based reverse dosimetry as a NAM to predict human cardiotoxicity.