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

Abstract

Background and Purpose: Cardiovascular safety is one of the most frequent causes of safety-related attrition both preclinically and clinically. Preclinical cardiovascular safety is routinely assessed using dog telemetry monitoring key cardiovascular functions. The present research was to develop a semi-mechanistic modelling platform to simultaneously assess changes in contractility (dPdt max), heart rate (HR) and mean arterial pressure (MAP) in preclinical studies. Experimental Approach: Data from dPdt max , HR, preload (left ventricular enddiastolic pressure [LVEDP]) and MAP were available from dog telemetry studies after dosing with atenolol (n = 27), salbutamol (n = 5), L-N G-nitroarginine methyl ester (L-NAME; n = 4), milrinone (n = 4), verapamil (n = 12), dofetilide (n = 8), flecainide (n = 4) and AZ001 (n = 14). Literature model for rat CV function was used for the structural population pharmacodynamic model development. LVEDP was evaluated as covariate to account for the effect of preload on dPdt max .

Mechanism-based pharmacodynamic model for propofol haemodynamic effects in healthy volunteers☆

“…Moreover, both models account for a potential time-varying effect that causes a temporary increase in HR and MAP. 12,13 The Snelder model was further extended by Venkatasubramanian and colleagues 14 based on data in dogs to include cardiac contractility (dPdt max ). In this refined model, a more detailed mechanistic description of SV was used that included cardiac contractility and HR.…”

“…Snelder and colleagues 12,13 have developed a PKePD model in rats that integrates a quantitative description of the physiology of the cardiovascular system and the effect of cardiovascular drugs on the relationship between MAP, TPR, HR, and stroke volume (SV). This model has been extended by including heart contractility data in dogs, 14 and recent models with similar structure perform reasonably well in humans. 15,16 We aimed to develop a mechanism-based PKePD model that describes the relationship between cardiovascular variables and propofol plasma concentrations using the principles outlined by Snelder and colleagues.…”

Mechanisms of flecainide induced negative inotropy: An in silico study

“…Most drug safety assessments associated with block of repolarization currents and consequent repolarization abnormalities. Even though more recent investigations into repolarization related safety pharmacology and its hallmark, the prolongation of the QT interval, have taken into account multi-channel block by drugs, there has not This important area of translational research is ripe for renewed investigation [6,37,10]. By assessing and revealing the fundamental ionic mechanisms associated with electrophysiological effects of flecainide and the resulting mechanical alterations, insights into promising development of new therapeutic interventions, or combinations of existing drugs used in appropriate doses may allow for minimization of unwanted side effects [47,48].…”

“…This important area of translational research is ripe for renewed investigation [ 6 , 37 , 10 ]. By assessing and revealing the fundamental ionic mechanisms associated with electrophysiological effects of flecainide and the resulting mechanical alterations, insights into promising development of new therapeutic interventions, or combinations of existing drugs used in appropriate doses may allow for minimization of unwanted side effects [ 47 , 48 ].…”

“…The focus on repolarization abnormalities in safety pharmacology screening has resulted in insufficient emphasis on closely related depolarization abnormalities and the potential side effects resulting from inhibition of sodium current, although some new technologies are emerging [6]. Such side effects include well-known conduction slowing, but in the ventricle other side effects are also recognized as important risk factors for drug safety [7][8][9][10].…”