PT  - JOURNAL ARTICLE
AU  - Sparve, Erik
AU  - Quartino, Angelica L.
AU  - Lüttgen, Maria
AU  - Tunblad, Karin
AU  - Gårdlund, Anna Teiling
AU  - Fälting, Johanna
AU  - Alexander, Robert
AU  - Kågström, Jens
AU  - Sjödin, Linnea
AU  - Bulgak, Alexander
AU  - Al-Saffar, Ahmad
AU  - Bridgland-Taylor, Matthew
AU  - Pollard, Chris
AU  - Swedberg, Michael D. B.
AU  - Vik, Torbjörn
AU  - Paulsson, Björn
TI  - Prediction and Modeling of Effects on the QTc Interval for Clinical Safety Margin Assessment, Based on Single-Ascending-Dose Study Data with AZD3839
AID  - 10.1124/jpet.114.215202
DP  - 2014 Aug 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 469--478
VI  - 350
IP  - 2
4099  - http://jpet.aspetjournals.org/content/350/2/469.short
4100  - http://jpet.aspetjournals.org/content/350/2/469.full
SO  - J Pharmacol Exp Ther2014 Aug 01; 350
AB  - 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.