Dual effect of clonidine on QT interval duration and body temperature in cynomolgus monkeys: QT correction formula for changes in core body temperature

Amrani, Abdelaziz; Huang, Hai; Loriot, Stéphane; Amrani, Francine El; Singh, Phirtu; Authier, Simon; Forster, Roy

doi:10.1016/j.vascn.2019.05.139

Cited by 1 publication

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“…In addition, direct QT effects may be missed when testing drugs that change body temperature. Correction methods have been devised ( van der Linde et al , 2008 ) and successfully applied ( El Amrani et al , 2019 ) to correct QT simultaneously for changes in heart rate and body temperature.…”

Section: Theoretical Reasons For the Lack Of Concordance Observed Bet...mentioning

confidence: 99%

The Challenges of Predicting Drug-Induced QTc Prolongation in Humans

Valentin

Hoffmann²,

Ortemann‐Renon

et al. 2022

Toxicological Sciences

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The content of this manuscript derives from a Health and Environmental Sciences Institute (HESI) consortium with a focus to improve cardiac safety during drug development. A detailed literature review was conducted to evaluate the concordance between non-clinical repolarization assays and the clinical thorough QT (TQT) study (Vargas et al., 2015). FDA and HESI developed a joint database of non-clinical and clinical data, and a retrospective analysis of 150 anonymized drug candidates was reviewed to compare performance of three standard non-clinical assays with clinical TQT study findings as well as investigate mechanism(s) potentially responsible for apparent discrepancies identified. The non-clinical assays were functional (IKr) current block (hERG), action potential duration (APD), and QTc interval in animals (in vivo QTc). While these non-clinical assays demonstrated good specificity for predicting negative clinical QT prolongation, they had relatively poor sensitivity for predicting positive clinical QT prolongation (Park et al., 2018). After review, 28 discordant TQT-positive drugs were identified. This manuscript provides an overview of direct and indirect mechanisms responsible for QT prolongation and theoretical reasons for lack of concordance between clinical TQT studies and non-clinical assays. We examine six specific and discordant TQT-positive drugs as case examples. These were derived from the unique HESI/FDA database. We would like to emphasize some reasons for discordant data including, insufficient or inadequate non-clinical data, effects of the drug on other cardiac ion channels, and indirect and/or non-electrophysiological effects of drugs, including altered heart rate. We also outline best practices that were developed based upon our evaluation.

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Section: Theoretical Reasons For the Lack Of Concordance Observed Bet...mentioning

confidence: 99%