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

Background
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 alkaloids ibogaine and its metabolite noribogaine, being promising anti-addiction drugs.

Methods
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 the 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 time duration from ventricular depolarization to repolarization) using PBK model based reverse dosimetry.

Results
Results showed that the predictions matched well with available in vivo kinetic data and QTc datafor ibogaine and noribogaine available in 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.

Conclusion
The present study provides an additional proof of principle of using PBK modeling-based reverse dosimetry as a NAM to predict human cardiotoxicity.