title: Evolving regulatory paradigm for proarrhythmic risk assessment for new drugs.
abstract: Fourteen drugs were removed from the market worldwide because their potential to cause torsade de pointes (torsade), a potentially fatal ventricular arrhythmia. The observation that most drugs that cause torsade block the potassium channel encoded by the human ether-à-go-go related gene (hERG) and prolong the heart rate corrected QT interval (QTc) on the ECG, led to a focus on screening new drugs for their potential to block the hERG potassium channel and prolong QTc. This has been a successful strategy keeping torsadogenic drugs off the market, but has resulted in drugs being dropped from development, sometimes inappropriately. This is because not all drugs that block the hERG potassium channel and prolong QTc cause torsade, sometimes because they block other channels. The regulatory paradigm is evolving to improve proarrhythmic risk prediction. ECG studies can now use exposure-response modeling for assessing the effect of a drug on the QTc in small sample size first-in-human studies. Furthermore, the Comprehensive in vitro Proarrhythmia Assay (CiPA) initiative is developing and validating a new in vitro paradigm for cardiac safety evaluation of new drugs that provides a more accurate and comprehensive mechanistic-based assessment of proarrhythmic potential. Under CiPA, the prediction of proarrhythmic potential will come from in vitro ion channel assessments coupled with an in silico model of the human ventricular myocyte. The preclinical assessment will be checked with an assessment of human phase 1 ECG data to determine if there are unexpected ion channel effects in humans compared to preclinical ion channel data. While there is ongoing validation work, the heart rate corrected J-Tpeakinterval is likely to be assessed under CiPA to detect inward current block in presence of hERG potassium channel block.
authors.affiliation: Office of Clinical Pharmacology, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, MD, USA. Electronic address: pepoviru@gmail.com.
authors.forename: Jose
authors.initials: J
authors.lastname: Vicente
authors.affiliation: Division of Cardiovascular and Renal Products, Office of New Drugs, U.S. Food and Drug Administration, Silver Spring, MD, USA.
authors.forename: Norman
authors.initials: N
authors.lastname: Stockbridge
authors.affiliation: Office of Clinical Pharmacology, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, MD, USA.
authors.forename: David G
authors.initials: DG
authors.lastname: Strauss
mesh_terms: D002309:Cardiology / Q000592:standards*; D004562:Electrocardiography / Q000592:standards*; D006801:Humans; D061214:Patient Safety / Q000592:standards; D017410:Practice Guidelines as Topic; D011358:Product Surveillance, Postmarketing / Q000592:standards*; D018570:Risk Assessment / Q000592:standards*; D016171:Torsades de Pointes / Q000139:chemically induced* / Q000175:diagnosis*; D014481:United States
keywords: J–T(peak)c; Multi-ion channel block; QTc prolongation; T-wave morphology; Torsade de pointes; hERG block