The Comprehensive In Vitro Proarrhythmia Assay Initiative
This chapter discusses the Comprehensive In Vitro Proarrhythmia Assay (CiPA) initiative, an integrated set of investigations that may lead to modifications of the nonclinical proarrhythmic cardiac safety regulatory landscape. Underlying this initiative is
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The Comprehensive In Vitro Proarrhythmia Assay Initiative These new strategies have the potential to improve sensitivity and specificity in the early detection of genuine cardiotoxicity risks, thereby reducing the likelihood of mistakenly discarding viable drug candidates and speeding the progression of worthy drugs into clinical trials (Gintant et al. 2016).
9.1 Introduction This chapter discusses the Comprehensive In Vitro Proarrhythmia Assay (CiPA) initiative, an integrated set of investigations that may lead to modifications of the nonclinical proarrhythmic cardiac safety regulatory landscape. Underlying this initiative is the fact that drug-induced IKr reduction and QTc interval prolongation are far from ideal surrogates for actual proarrhythmic risk, the true concern in the domain of proarrhythmic cardiac safety. The link between drug-induced QTc prolongation and the rare (but potentially lethal) arrhythmia torsades appears to be multifaceted, and occurrence of drug-induced torsades typically requires multiple contributing factors to be present simultaneously. Some of these clinical risk factors include female sex, structural heart disease, metabolic and electrolyte abnormalities, bradycardia and pauses, increased concentrations of “culprit” drugs, and inherited syndromes causing QT prolongation (Vlachos et al. 2016). Sager and colleagues (2014) therefore observed that, given our advancing knowledge and understanding on multiple fronts, it is incumbent upon us to provide a more comprehensive evaluation of actual proarrhythmic risk. These advances are evident in our knowledge of mechanisms responsible for torsades, our ability to evaluate drug effects on human cardiac ion channels, successes in in silico modeling of human ventricular electrical activity, and the evolving employment of isolated human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). The CiPA paradigm is comprised of three fundamental components: a two- component core in vitro strategy assessing effects on isolated cardiac currents and integrated drug responses from hiPSC-CMs and in silico reconstructions of cellular electrophysiological activity. An additional step is the definition of the proarrhythmic risk of a select group of drugs used clinically, thereby defining a “gold standard” © Springer International Publishing Switzerland 2017 J.R. Turner et al., Cardiovascular Safety in Drug Development and Therapeutic Use, DOI 10.1007/978-3-319-40347-2_9
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for comparison of nonclinical and clinical findings. Organized as a public–private collaboration, CiPA represents a mechanistic-based set of investigations that will provide a better understanding of a drug’s proarrhythmic liability. The initiative is being driven by an international consortium comprising multiple collaborators including the FDA, EMA, Health Canada, PMDA, CSRC, the Health and Environmental Sciences Institute (HESI), the Safety Pharmacology Society (SPS), Japan National Institute of Health
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