دورية أكاديمية
Optimized J to T peak and T peak to T end measurements in nonclinical species administered moxifloxacin and amiodarone.
| العنوان: | Optimized J to T peak and T peak to T end measurements in nonclinical species administered moxifloxacin and amiodarone. |
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| المؤلفون: | Bartko TM; Labcorp Early Development Laboratories Inc., Madison, WI, United States of America. Electronic address: theresa.bartko@labcorp.com., Lutgen SM; Labcorp Early Development Laboratories Inc., Madison, WI, United States of America., Ross RA; Labcorp Early Development Laboratories Inc., Madison, WI, United States of America., Walisser JA; Labcorp Early Development Laboratories Inc., Madison, WI, United States of America., Garske EP; Labcorp Early Development Laboratories Inc., Madison, WI, United States of America., Kopelke KR; Labcorp Early Development Laboratories Inc., Madison, WI, United States of America., Ashcroft-Hawley K; Labcorp Early Development Laboratories Ltd., Harrogate, UK., Tang HM; Novartis Pharmaceuticals Corporation, East Hanover, NJ, United States of America., Kremer JJ; Novartis Pharmaceuticals Corporation, East Hanover, NJ, United States of America., Friedrichs GS; Novartis Pharmaceuticals Corporation, East Hanover, NJ, United States of America., Nichols JV; Labcorp Early Development Laboratories Inc., Madison, WI, United States of America. |
| المصدر: | Journal of pharmacological and toxicological methods [J Pharmacol Toxicol Methods] 2024 Jul-Aug; Vol. 128, pp. 107527. Date of Electronic Publication: 2024 Jun 08. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: Elsevier Country of Publication: United States NLM ID: 9206091 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1873-488X (Electronic) Linking ISSN: 10568719 NLM ISO Abbreviation: J Pharmacol Toxicol Methods Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: New York, NY : Elsevier, c1992- |
| مواضيع طبية MeSH: | Moxifloxacin*/administration & dosage , Moxifloxacin*/pharmacology , Amiodarone*/administration & dosage , Amiodarone*/pharmacology , Electrocardiography*/drug effects , Electrocardiography*/methods , Torsades de Pointes*/chemically induced , Long QT Syndrome*/chemically induced , Long QT Syndrome*/physiopathology, Animals ; Dogs ; Male ; Ether-A-Go-Go Potassium Channels/antagonists & inhibitors ; Ether-A-Go-Go Potassium Channels/metabolism ; Female ; Macaca fascicularis ; Fluoroquinolones/administration & dosage ; Fluoroquinolones/pharmacology ; Heart Rate/drug effects ; Potassium Channel Blockers/administration & dosage ; Potassium Channel Blockers/pharmacology ; ERG1 Potassium Channel/antagonists & inhibitors ; ERG1 Potassium Channel/metabolism |
| مستخلص: | Introduction: Cardiovascular safety and the risk of developing the potentially fatal ventricular tachyarrhythmia, Torsades de Pointes (TdP), have long been major concerns of drug development. TdP is associated with a delayed ventricular repolarization represented by QT interval prolongation in the electrocardiogram (ECG), typically due to block of the potassium channel encoded by the human ether-a-go-go related gene (hERG). Importantly however, not all drugs that prolong the QT interval are torsadagenic and not all hERG blockers prolong the QT interval. Recent clinical reports suggest that partitioning the QT interval into early (J to T peak; JTp) and late repolarization (T peak to T end; TpTe) components may be valuable for distinguishing low-risk mixed ion channel blockers (hERG plus calcium and/or late sodium currents) from high-risk pure hERG channel blockers. This strategy, if true for nonclinical animal models, could be used to de-risk QT prolonging compounds earlier in the drug development process. Methods: To explore this, we investigated JTp and TpTe in ECG data collected from telemetered dogs and/or monkeys administered moxifloxacin or amiodarone at doses targeting relevant clinical exposures. An optimized placement of the Tpeak fiducial mark was utilized, and all intervals were corrected for heart rate (QTc, JTpc, TpTec). Results: Increases in QTc and JTpc intervals with administration of the pure hERG blocker moxifloxacin and an initial QTc and JTpc shortening followed by prolongation with the mixed ion channel blocker amiodarone were detected as expected, aligning with clinical data. However, anticipated increases in TpTec by both standard agents were not detected. Discussion: The inability to detect changes in TpTec reduces the utility of these subintervals for prediction of arrhythmias using continuous single‑lead ECGs collected from freely moving dogs and monkeys. Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. (Copyright © 2023. Published by Elsevier Inc.) |
| فهرسة مساهمة: | Keywords: Amiodarone; Dog; ECG; JTp; Methods; Monkey; Moxifloxacin; QTc; Torsades; TpTe |
| المشرفين على المادة: | U188XYD42P (Moxifloxacin) N3RQ532IUT (Amiodarone) 0 (Ether-A-Go-Go Potassium Channels) 0 (Fluoroquinolones) 0 (Potassium Channel Blockers) 0 (ERG1 Potassium Channel) |
| تواريخ الأحداث: | Date Created: 20240609 Date Completed: 20240729 Latest Revision: 20240729 |
| رمز التحديث: | 20240730 |
| DOI: | 10.1016/j.vascn.2024.107527 |
| PMID: | 38852685 |
| قاعدة البيانات: | MEDLINE |
Full Text Finder | تدمد: | 1873-488X |
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| DOI: | 10.1016/j.vascn.2024.107527 |