title: Evaluation of drug-induced QT interval prolongation in animal and human studies: a literature review of concordance.
abstract: Evaluating whether a new medication prolongs QT intervals is a critical safety activity that is conducted in a sensitive animal model during non-clinical drug development. The importance of QT liability detection has been reinforced by non-clinical [International Conference on Harmonization (ICH) S7B] and clinical (ICH E14) regulatory guidance from the International Conference on Harmonization. A key challenge for the cardiovascular safety community is to understand how the finding from a non-clinical in vivo QT assay in animals predicts the outcomes of a clinical QT evaluation in humans. The Health and Environmental Sciences Institute Pro-Arrhythmia Working Group performed a literature search (1960-2011) to identify both human and non-rodent animal studies that assessed QT signal concordance between species and identified drugs that prolonged or did not prolong the QT interval. The main finding was the excellent agreement between QT results in humans and non-rodent animals. Ninety-one percent (21 of 23) of drugs that prolonged the QT interval in humans also did so in animals, and 88% (15 of 17) of drugs that did not prolong the QT interval in humans had no effect on animals. This suggests that QT interval data derived from relevant non-rodent models has a 90% chance of predicting QT findings in humans. Disagreement can occur, but in the limited cases of QT discordance we identified, there appeared to be plausible explanations for the underlying disconnect between the human and non-rodent animal QT outcomes.
authors.affiliation: Integrated Discovery and Safety Pharmacology, Amgen, Inc., Thousand Oaks, CA, USA.
authors.forename: Hugo M
authors.initials: HM
authors.lastname: Vargas
authors.affiliation: Safety Assessment, Merck Research Laboratories, Boston, MA, USA.
authors.forename: Alan S
authors.initials: AS
authors.lastname: Bass
authors.affiliation: Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD, USA.
authors.forename: John
authors.initials: J
authors.lastname: Koerner
authors.affiliation: Discovery Information, AstraZeneca R&D, Wilmington, DE, USA.
authors.forename: Sherri
authors.initials: S
authors.lastname: Matis-Mitchell
authors.affiliation: Safety and Exploratory Pharmacology, Janssen R&D, Raritan, NJ, USA.
authors.forename: Michael K
authors.initials: MK
authors.lastname: Pugsley
authors.affiliation: Safety Assessment, AstraZeneca R&D, Cheshire, UK.
authors.forename: Matthew
authors.initials: M
authors.lastname: Skinner
authors.affiliation: Safety Assessment, AstraZeneca R&D, Cheshire, UK.
authors.forename: Matthew
authors.initials: M
authors.lastname: Burnham
authors.affiliation: Safety Assessment, AstraZeneca R&D, Cheshire, UK.
authors.forename: Matthew
authors.initials: M
authors.lastname: Bridgland-Taylor
authors.affiliation: Health and Environmental Sciences Institute, Washington, DC, USA.
authors.forename: Syril
authors.initials: S
authors.lastname: Pettit
authors.affiliation: Safety Assessment, AstraZeneca R&D, Cheshire, UK.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Valentin
mesh_terms: D000818:Animals; D004353:Drug Evaluation, Preclinical; D006801:Humans; D008133:Long QT Syndrome / Q000139:chemically induced*; D012680:Sensitivity and Specificity