A new approach methodology (NAM) for the prediction of (nor)ibogaine-induced cardiotoxicity in humans.

A non-animal approach combining lab-grown human heart cells with computer modeling accurately predicted the heart side effects of two anti-addiction drugs, ibogaine and its metabolite noribogaine. The method used human stem cell-derived heart cells on a multi-electrode array to measure concentration-dependent prolongation of field potential duration, a sign of cardiotoxicity. Physiologically based kinetic models then translated these lab results into predicted dose-dependent QTc prolongation in humans. The predictions matched published human data, demonstrating that this new approach methodology can replace animal testing for cardiac safety evaluation.

Study at a glance

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.