Technological Advances in Cardiovascular Safety Assessment Decrease Preclinical Animal Use and Improve Clinical Relevance.

Cardiovascular (CV) safety liabilities are significant concerns for drug developers and preclinical animal studies are predominately where those liabilities are characterized before patient exposures. Steady progress in technology and laboratory capabilities is enabling a more refined and informative use of animals in those studies. The application of surgically implantable and telemetered instrumentation in the acute assessment of drug effects on CV function has significantly improved historical approaches that involved anesthetized or restrained animals.

The evaluation of drug-induced changes in cardiac inotropy in dogs: Results from a HESI-sponsored consortium.

Introduction: Drug-induced effects on the cardiovascular system remain a major cause of drug attrition. While hemodynamic (blood pressure (BP) and heart rate (HR)) and electrophysiological methods have been used in testing drug safety for years, animal models for assessing myocardial contractility are used less frequently and their translation to humans has not been established. The goal of these studies was to determine whether assessment of contractility and hemodynamics, when measured across different laboratories using the same protocol, could consistently detect drug-induced changes in the inotropic state of the heart using drugs known to have clinically relevant positive and negative effects on myocardial contractility.

Cardiovascular pressure measurement in safety assessment studies: technology requirements and potential errors.

In the early days of in vivo nonclinical pressure measurement, most laboratories were required to have considerable technical/engineering expertise to configure and maintain pressure transducers, amplifiers, tape recorders, chart recorders, etc. Graduate students and postdoctoral fellows typically had some training in the requirements and limitations of the technology they used and were closely engaged in the collection and evaluation of data from their own experiments. More recently, pressure sensing telemetry and data acquisition/analysis systems are provided by vendors as turnkey systems, often resulting in a situation where users are less familiar with the technicalities of their operation.

A public-private consortium advances cardiac safety evaluation: achievements of the HESI Cardiac Safety Technical Committee.

Introduction: The evaluation of cardiovascular side-effects is a critical element in the development of all new drugs and chemicals. Cardiac safety issues are a major cause of attrition and withdrawal due to adverse drug reactions (ADRs) in pharmaceutical drug development.

Methods: The evolution of the HESI Technical Committee on Cardiac Safety from 2000-2013 is presented as an example of an effective international consortium of academic, government, and industry scientists working to improve cardiac safety.

Left ventricular pressure, contractility and dP/dt(max) in nonclinical drug safety assessment studies.

Increasing or decreasing cardiac contractility is an undesirable property of drugs being developed for noncardiovascular indications. The International Conference on Harmonization (ICH) Topic S7A and S7B guidelines only require the assessment of heart rate, blood pressure and the electrocardiogram in nonclinical in vivo safety pharmacology studies. Assessment of drug effects on contractility is only suggested as an optional follow-up study.