Comparison of Zebrafish Larvae and hiPSC Cardiomyocytes for Predicting Drug-Induced Cardiotoxicity in Humans.

Sylvia Dyballa,Georgia Escaramis,Tiziana Pederzani,Rafael Miñana,Carles Cornet,Javier Terriente,Ricard Garcia-Serna,Maria Rubio-Brotons,Jordi Mestres

doi:10.1093/toxsci/kfz165

Abstract

Cardiovascular drug toxicity is responsible for 17% of drug withdrawals in clinical phases, half of post-marketed drug withdrawals and remains an important adverse effect of several marketed drugs. Early assessment of drug-induced cardiovascular toxicity is mandatory and typically done in cellular systems and mammals. Current in vitro screening methods allow high-throughput but are biologically reductionist. The use of mammal models, which allow a better translatability for predicting clinical outputs, is low-throughput, highly expensive, and ethically controversial. Given the analogies between the human and the zebrafish cardiovascular systems, we propose the use of zebrafish larvae during early drug discovery phases as a balanced model between biological translatability and screening throughput for addressing potential liabilities. To this end, we have developed a high-throughput screening platform that enables fully automatized in vivo image acquisition and analysis to extract a plethora of relevant cardiovascular parameters: heart rate, arrhythmia, AV blockage, ejection fraction, and blood flow, among others. We have used this platform to address the predictive power of zebrafish larvae for detecting potential cardiovascular liabilities in humans. We tested a chemical library of 92 compounds with known clinical cardiotoxicity profiles. The cross-comparison with clinical data and data acquired from human induced pluripotent stem cell cardiomyocytes calcium imaging showed that zebrafish larvae allow a more reliable prediction of cardiotoxicity than cellular systems. Interestingly, our analysis with zebrafish yields similar predictive performance as previous validation meta-studies performed with dogs, the standard regulatory preclinical model for predicting cardiotoxic liabilities prior to clinical phases.

Highlights

Adverse effects from drugs represent a heavy burden for the healthcare sector
Each report in FAERS contains data on the main drug believed to be responsible of the safety event(s) collected, the list of concomitant drugs coadministered to the patient, the list of safety events suffered by the patient, the therapeutic indication(s) for which the drugs were prescribed, the administration route, the gender, age, and weight of the patient, the clinical output, the actual reporter, and the event and deposit dates
This potential application, we have performed a cross-comparison of the predictive performance to unveil human cardiotoxic liabilities between the in vivo zebrafish model and a traditional in vitro hiPSC-CM model

Summary

Introduction

Adverse effects from drugs represent a heavy burden for the healthcare sector. Among the different types of drug-induced toxicities, cardiovascular toxicity is responsible for 17.4% of clinical stage withdrawals (Fung et al, 2001), and 46% of post-marketed drug withdrawals (Stevens and Baker, 2009). In later phases of drug development, large mammalian models, mainly dogs, remain the gold standard for cardiotoxicity testing (Blomme and Will, 2016) Preclinical testing in those large mammals is crucial and compulsory by regulatory agencies to grant access to clinical phases. The use of small rodents, such as mice and rats, provides a slightly higher throughput than dogs, but their physiological differences with humans generate doubts about their predictive performance (Blomme and Will, 2016) In addition to those concerns, the use of mammals for cardiotoxicity testing impacts negatively on the industry efforts for implementing animal research replacement, reduction, and refinement (3R) measures

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Results

Conclusion