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

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/dt max ) 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.

Chronic cardiotoxicity assessment of BMS-986094, a guanosine nucleotide analogue, using human iPS cell-derived cardiomyocytes

“…To date, we have successfully performed validation studies to assess drug-induced proarrhythmic risk in nonclinical settings (Ando et al, 2017;Blinova et al, 2018;Gintant et al, 2020;Kanda et al, 2018). In addition to proarrhythmic risk assessment, cardiac contractility changes play a key role in drug development in terms of acute cardiotoxicity and chronic effects (Guth et al, 2019;Ribeiro et al, 2019). Several studies have assessed the acute effects of drugs on hiPSC-CMs contractions using various platforms (Hayakawa et al, 2014;Scott et al, 2014).…”

Heart Slices to Model Cardiac Physiology

“…Additionally, the applicability of the system to human cells is of paramount importance. Guth et al ( Guth et al, 2019 ) summarized the most relevant features and considerations for in-vivo drug testing platforms.…”

“…The most prevalently used cardiac physiology screening platform are animal models that have limited reliability in mirroring the effects of drugs in human hearts ( Liu et al, 2006 ; Salama and Bett, 2014 ). Additionally, the use of animal models to create a pharmacokinetic profile of drugs is relatively expensive at the early development stage since large amounts of the drugs are used ( Guth et al, 2019 ). Ultimately, the ideal experimental cardiac model is one that demonstrates high sensitivity and specificity toward various therapeutic and pharmacological interventions while accurately replicating the physiology and pathophysiology of the human heart ( Wang et al, 2008 ).…”

Direct Contraction Force Measurements of Engineered Cardiac Tissue Constructs With Inotropic Drug Exposure

“…Currently, in vitro cardiotoxicity and efficacy testing of drugs lack standardized testing methods for drug-induced inotropic effects on cardiac cells, even though the cardiac contractility directly affects the cardiac output ( Guth et al, 2019 ). Approaches to measure cardiac contraction force in vitro include different imaging-based approaches ( Rodriguez et al, 2014 ; Mannhardt et al, 2016 ) and direct force measurements such as atomic force microscope ( Saenz Cogollo et al, 2011 ), measuring the deflection of an elastic sheet ( Linder et al, 2010 ), and piezoresistive sensor–integrated polydimethylsiloxane (PDMS) cantilever ( Kim et al, 2017 ).…”