1. Evaluation of cardiac function in unrestrained dogs and monkeys using left ventricular dP/dt.
- Author
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Buchanan LV, Warner WA, Arthur SR, Gleason CR, Lewen G, Levesque PC, and Gill MW
- Subjects
- Animals, Anti-Arrhythmia Agents pharmacology, Atenolol pharmacology, Blood Pressure drug effects, Cardiotonic Agents pharmacology, Dogs, Drug Evaluation, Preclinical, Female, Heart Rate drug effects, Macaca fascicularis, Male, Myocardial Contraction, Pyridazines pharmacology, Reference Values, Telemetry, Heart drug effects, Heart Function Tests methods, Ventricular Function, Left drug effects
- Abstract
Introduction: Preclinical assessment for alterations in cardiac ventricular function for drug candidates has not been a focus of ICH S7b guidelines for cardiovascular safety studies, but there is growing interest given that the cardiovascular risk is associated with positive and negative inotropes., Methods: From 2003 through 2013, 163 telemetry studies with left-ventricular function analyses were conducted in dogs and monkeys at Bristol Myers Squibb (BMS) in support for drug development programs. The ability of the telemetry system to detect changes in cardiac contractility was verified with positive control agents pimobendan and atenolol. Control data from a subset of studies were analyzed to determine dP/dt reference range values, and minimum detectable mean differences (control vs. treated) for statistical significance., Results: Median minimum detectable differences for dogs ranged from 14 to 21% for positive dP/dt and 11 to 21% for negative dP/dt. For monkeys, median minimum detectable differences were 25 and 14% for positive and negative dP/dt, respectively. For BMS programs, 15 drug candidates were identified that produced primary effects on contractility. Changes in contractility that were associated with, and potentially secondary to, drug-related effects on heart rate or systemic blood pressure were observed with an additional 29 drug candidates., Discussion: Changes in contractility have been observed in large animals during drug development studies at BMS over the past 10years. Model sensitivity has been demonstrated and a dP/dt beat-to-beat cloud analysis tool has been developed to help distinguish primary effects from those potentially secondary to systemic hemodynamic changes., (Copyright © 2016 Elsevier Inc. All rights reserved.)
- Published
- 2016
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