Considerations for an In Vitro, Cell-Based Testing Platform for Detection of Adverse Drug-Induced Inotropic Effects in Early Drug Development. Part 1: General Considerations for Development of Novel Testing Platforms.

Brian D Guth,Yasunari Kanda,John Koerner,Alexandre J S Ribeiro,Stanley T Parish,Michael Engwall,Brian Berridge,Gary Gintant,Khuram W Chaudhary,C Michael Foley,Tanja Zabka,Liang Guo,Sandy Eldridge,Jennifer B Pierson

doi:10.3389/fphar.2019.00884

Abstract

Drug-induced effects on cardiac contractility can be assessed through the measurement of the maximal rate of pressure increase in the left ventricle (LVdP/dtmax) in conscious animals, and such studies are often conducted at the late stage of preclinical drug development. Detection of such effects earlier in drug research using simpler, in vitro test systems would be a valuable addition to our strategies for identifying the best possible drug development candidates. Thus, testing platforms with reasonably high throughput, and affordable costs would be helpful for early screening purposes. There may also be utility for testing platforms that provide mechanistic information about how a given drug affects cardiac contractility. Finally, there could be in vitro testing platforms that could ultimately contribute to the regulatory safety package of a new drug. The characteristics needed for a successful cell or tissue-based testing platform for cardiac contractility will be dictated by its intended use. In this article, general considerations are presented with the intent of guiding the development of new testing platforms that will find utility in drug research and development. In the following article (part 2), specific aspects of using human-induced stem cell-derived cardiomyocytes for this purpose are addressed.

Highlights

Cardiovascular (CV) safety liabilities of new drugs are an important source of attrition during development and may have severe consequences for patients if compounds progress to clinical testing and even market approval
A prospective description of the needed characteristics of such a test system would help guide the design of these systems. It must be considered for which purpose a test system will be employed; we propose three basic potential uses of these systems
The detection and avoidance of unwanted drug-induced effects on cardiac contractility have become of increasing importance in the search for novel and safe drugs (Guth et al, 2015)

Summary

Introduction

Cardiovascular (CV) safety liabilities of new drugs (real or presumptive) are an important source of attrition during development and may have severe consequences for patients if compounds progress to clinical testing and even market approval. The demonstration of CV safety in preclinical studies is a cornerstone of the safety pharmacology assessment performed prior to first-in-human trials. Despite the proven utility and relevance of in vivo animal systems for testing for CV effects, some liabilities have only been recognized in patients, with their varied susceptibilities (i.e., age, gender, genetics, etc.) and co-morbidities that are poorly modeled in healthy animals. Current International Council for Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) guidelines (e.g., ICHS7A) focus on the evaluation of hemodynamic effects including heart rate and systemic arterial blood pressure. The assessment of drug-induced inotropic effects on the myocardium is not currently a routine regulatory expectation based on preclinical safety guidelines, evaluation of potential inotropic effects in vivo is recognized as an essential safety endpoint in drug development (Guth et al, 2015). The purpose of this article is to describe the necessary characteristics of a successful in vitro test system for employment in the context of its positioning and use within the workflows of drug research and development

Objectives

Findings

Conclusion