Semi‐mechanistic modelling platform to assess cardiac contractility and haemodynamics in preclinical cardiovascular safety profiling of new molecular entities

Abstract

Background and Purpose Cardiovascular (CV) safety is one of the most frequent causes of safety related attrition both pre‐clinically and clinically. Preclinical cardiovascular safety, routinely assessed using dog telemetry as part of the safety pharmacology package, monitors key cardiac and hemodynamic functions. The objective of this effort was to develop a semi‐mechanistic modeling platform to simultaneously assess changes in contractility (dPdt_max), heart rate (HR) and mean arterial pressure (MAP) in preclinical studies. Methods Data from dPdt_max, HR, preload (left ventricular end‐diastolic pressure; LVEDP) and MAP were available from dog telemetry studies after dosing with atenolol (n=27), albuterol (n=5), L­NG­Nitroarginine Methyl Ester (L­NAME; n=4), milrinone (n=4), verapamil (n=12), dofetilide (n=8), flecainide (n=4) and AZ001 (n=14). Literature models for rat CV function was used as a starting point for the structural population pharmacodynamic model development. LVEDP was evaluated as covariate to account for the effect of preload on dPdt_max. Key Results The model was able to describe drug‐induced changes in dPdt_max, HR and MAP for all drugs included in the developed framework adequately by incorporating appropriate drug effects on either dPdt_max, HR and/or TPR. Consistent with the Starling’s law, incorporation of LVEDP as a covariate on dPdt_max to correct for the pre‐load effect was found to be statistically significant. Conclusions and Implications The contractility and hemodynamics semi‐mechanistic modeling platform accounts for diurnal variation, drug induced changes and inter‐animal variation. The model can be used to hypothesize and evaluate pharmacological effects and to provide a holistic cardiovascular safety profile for new molecular entities.