title: A Quantitative Framework to Evaluate Proarrhythmic Risk in a First-in-Human Study to Support Waiver of a Thorough QT Study.
abstract: The effects of GS-4997 (apoptosis signal-regulating kinase 1 inhibitor) on cardiac repolarization were evaluated using a systematic modeling approach in a first-in-human (FIH) study. High quality, intensive, time-matched 12-lead electrocardiograms (ECGs) were obtained in this placebo-controlled, single and multiple-ascending dose study in healthy subjects. Model development entailed linearity and hysteresis assessments; GS-4997/metabolite concentration vs. baseline-adjusted QTcF (ΔQTcF) relationships were determined using linear mixed effects models. Bootstrapping was used to obtain 90% confidence intervals (CIs) of predicted placebo-corrected ΔQTcF (ΔΔQTcF). The upper bound of 90% CI for predicted ΔΔQTcF was <10 msec at therapeutic and supratherapeutic GS-4997/metabolite levels, indicating the absence of a QT prolongation effect. Model performance/suitability was assessed using sensitivity/specificity analyses and diagnostic evaluations. This comprehensive methodology, supported by clinical pharmacology characteristics, was deemed adequate to assess the proarrhythmic risk of GS-4997/metabolite by the US Food and Drug Administration and European Medicines Agency resulting in a successful waiver from a dedicated thorough QT (TQT) study.
authors.affiliation: Gilead Sciences, Foster City, California, USA.
authors.forename: C H
authors.initials: CH
authors.lastname: Nelson
authors.affiliation: Gilead Sciences, Foster City, California, USA.
authors.forename: L
authors.initials: L
authors.lastname: Wang
authors.affiliation: Gilead Sciences, Foster City, California, USA.
authors.forename: L
authors.initials: L
authors.lastname: Fang
authors.affiliation: Gilead Sciences, Foster City, California, USA.
authors.forename: W
authors.initials: W
authors.lastname: Weng
authors.affiliation: Gilead Sciences, Foster City, California, USA.
authors.forename: F
authors.initials: F
authors.lastname: Cheng
authors.affiliation: Gilead Sciences, Foster City, California, USA.
authors.forename: M
authors.initials: M
authors.lastname: Hepner
authors.affiliation: Gilead Sciences, Foster City, California, USA.
authors.forename: J
authors.initials: J
authors.lastname: Lin
authors.affiliation: Certara, St. Louis, Missouri, USA.
authors.forename: C
authors.initials: C
authors.lastname: Garnett
authors.affiliation: Gilead Sciences, Foster City, California, USA.
authors.forename: S
authors.initials: S
authors.lastname: Ramanathan
mesh_terms: D000200:Action Potentials; D001145:Arrhythmias, Cardiac / Q000139:chemically induced* / Q000175:diagnosis / Q000503:physiopathology; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D017277:Drug Approval; D004562:Electrocardiography; D005260:Female; D006329:Heart Conduction System / Q000187:drug effects* / Q000503:physiopathology; D006339:Heart Rate / Q000187:drug effects*; D006801:Humans; D016014:Linear Models; D008297:Male; D008954:Models, Biological; D009010:Monte Carlo Method; D047428:Protein Kinase Inhibitors / Q000009:adverse effects*; D018570:Risk Assessment; D012307:Risk Factors; D013997:Time Factors; D014481:United States; D014486:United States Food and Drug Administration
chemical_list: D047428:Protein Kinase Inhibitors