TY - JOUR T1 - Prediction and Modeling of Effects on the QTc Interval for Clinical Safety Margin Assessment, Based on Single-Ascending-Dose Study Data with AZD3839 JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 469 LP - 478 DO - 10.1124/jpet.114.215202 VL - 350 IS - 2 AU - Erik Sparve AU - Angelica L. Quartino AU - Maria Lüttgen AU - Karin Tunblad AU - Anna Teiling Gårdlund AU - Johanna Fälting AU - Robert Alexander AU - Jens Kågström AU - Linnea Sjödin AU - Alexander Bulgak AU - Ahmad Al-Saffar AU - Matthew Bridgland-Taylor AU - Chris Pollard AU - Michael D. B. Swedberg AU - Torbjörn Vik AU - Björn Paulsson Y1 - 2014/08/01 UR - http://jpet.aspetjournals.org/content/350/2/469.abstract N2 - Corrected QT interval (QTc) prolongation in humans is usually predictable based on results from preclinical findings. This study confirms the signal from preclinical cardiac repolarization models (human ether-a-go-go-related gene, guinea pig monophasic action potential, and dog telemetry) on the clinical effects on the QTc interval. A thorough QT/QTc study is generally required for bioavailable pharmaceutical compounds to determine whether or not a drug shows a QTc effect above a threshold of regulatory interest. However, as demonstrated in this AZD3839 [(S)-1-(2-(difluoromethyl)pyridin-4-yl)-4-fluoro-1-(3-(pyrimidin-5-yl)phenyl)-1H-isoindol-3-amine hemifumarate] single-ascending-dose (SAD) study, high-resolution digital electrocardiogram data, in combination with adequate efficacy biomarker and pharmacokinetic data and nonlinear mixed effects modeling, can provide the basis to safely explore the margins to allow for robust modeling of clinical effect versus the electrophysiological risk marker. We also conclude that a carefully conducted SAD study may provide reliable data for effective early strategic decision making ahead of the thorough QT/QTc study. ER -