QT Ratio: A simple solution to individual QT correction.

Autor: Ether ND; Pharmacology & Toxicology Department, College of Veterinary Medicine, Michigan State University, East Lansing, MI 48824, USA. Electronic address: ether@msu.edu., Leishman DJ; Eli Lilly and Co., Indianapolis, IN 46285, USA. Electronic address: derek.leishman@lilly.com., Bailie MB; Integrated Drug Development, CERTARA, Ann Arbor, MI 48103, USA. Electronic address: marc.bailie@certara.com., Lauver DA; Pharmacology & Toxicology Department, College of Veterinary Medicine, Michigan State University, East Lansing, MI 48824, USA. Electronic address: lauverda@msu.edu.
Jazyk: angličtina
Zdroj: Journal of pharmacological and toxicological methods [J Pharmacol Toxicol Methods] 2022 Sep-Oct; Vol. 117, pp. 107211. Date of Electronic Publication: 2022 Aug 22.
DOI: 10.1016/j.vascn.2022.107211
Abstrakt: Preclinical risk assessment of drug-induced arrhythmias is critical for drug development and relies on heart rate corrected QT interval (QT) prolongation as a biomarker for arrhythmia risk. However, the methods used to correct QT vary in complexity and don't account for all changes in the QT-rate relationship. Thus, we developed the novel Ratio QT correction method which characterizes that relationship at each timepoint using the ratio between QT, adjusted for a species-specific constant, and rate (RR interval). This ratio represents the slope between the intercept and the datapoint being corrected, which is then used in a linear equation like individual methods. A unique correction coefficient for each datapoint avoids assuming static relationships. We hypothesize that the simple and dynamic nature of the Ratio method will provide more consistent rate correction and error reduction compared to Bazett's and individual regression methods. Comparisons were made using ECG data from non-human primates (NHPs) treated with dofetilide or moxifloxacin, separated into small groups (n = 4). The methods were compared based on corrected QT vs RR slopes, standard error, and minimal detectable difference (MDD) for each method. The Ratio method resulted in smaller corrected QT-rate relationship slopes than Bazett's, more closely matching those of individual methods. It produced similar or lower MDDs compared to individual and Bazett's correction, respectively, with more consistent reduction in standard error. This simple and effective method has the potential for easy translatability across species.
Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Nicholas Ether reports financial support was provided by Eli Lilly and Company.
(Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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