A Role For in Vitro Disease Models in the Landscape of Preclinical Cardiotoxicity and Safety Testing - A Role For in Vitro Disease Models in the Landscape of Preclinical Cardiotoxicity and Safety Testing - Open Access Pub

Drug-induced cardiotoxicity is one of the predominant reasons for drug attrition and withdrawals. This is of critical concern when potentially cardiotoxic drugs are administered to individuals with inherited arrhythmogenic cardiac diseases or with metabolic diseases such as obesity and diabetes, which are key risk factors for cardiovascular diseases. Pathophysiological alteration prevalent under such conditions can alter or exacerbate cardiotoxic responses. The growing incidence of obesity, diabetes and metabolic syndrome subject a significant percentage of the population to drug treatments, thereby augmenting their risk for drug-induced cardiovascular toxicity. Hence, screening for drug-induced cardiotoxicity early in the preclinical stages of drug development, by using appropriate human disease models, can be effective in ensuring safety in clinical trials and preventing late stage and post-marketing drug withdrawals owing to cardiotoxicity. The advent of human pluripotent stem cells (hPSC) and induced pluripotent stem cell (iPSC)-derived cardiomyocytes are revolutionizing safety/toxicity screening in human cells by providing relevant human-specific, renewable model systems to explore human drug toxicity. The ability to generate patient-specific iPSCs that can model cardiac diseases, now offers a valuable option that can further improve drug safety assessments and enable a more accurate prediction of toxicity that occurs in the representative population that are prescribed the drugs. Use of appropriate disease models will not only provide cost savings by decreasing potential drug attrition and withdrawals, seen with many drugs, but will also be a promising option to advance precision medicine DOI10.14302/issn.2574-4372.jesr-17-1705 The drug development pipeline is an arduous, labor-intensive and expensive process that entails stringent regulations by the FDA, in order to ensure the final marketed drug will be safe and efficacious for use in all patients that are prescribed the drugs 1, 2, 3. Although rigorous screening and testing of drugs occur as part of preclinical studies and clinical trials, safety and toxicity continue to be leading causes for the withdrawal of drugs from the markets 1, 4, 5. Amongst specific organ toxicities, cardiac toxicity is one of the predominant reasons for late-stage attrition of drugs 6, 7, 8. A potential reason for late-stage drug attrition and post-marketing withdrawals may be attributed to drug-induce cardiotoxicity augmented by cardiovascular risk factors that are prevalent in many patients with metabolic disorders