Kinase inhibitor-induced cardiotoxicity assessed in vitro with human pluripotent stem cell derived cardiomyocytes

Area of Science:

• Cardiovascular Toxicology
• Drug Development
• Stem Cell Biology

Background:

• Small molecule kinase inhibitors (SMKIs) used in cancer therapy can cause severe cardiac adverse events.
• Traditional preclinical assays fail to adequately identify these cardiac liabilities.
• Improved prediction of drug-induced cardiotoxicity is crucial for safer drug development.

Purpose of the Study:

• To evaluate the predictive value of combined electrophysiological and non-electrophysiological assays using human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) for SMKI cardiotoxicity.
• To compare the efficacy of these combined assays against traditional methods, including the hERG assay.
• To provide early mechanistic insights into drug-induced cardiotoxicity during preclinical development.

Main Methods:

• Utilized hPSC-CMs in microplate-based assays to assess non-electrophysiological toxicities (cell death, apoptosis, mitochondrial damage, energy depletion, oxidative stress).
• Employed microelectrode arrays (MEAs) to measure electrophysiological effects like in vitro arrhythmic events (iAEs), field potential duration (FPD) prolongation, and spike amplitude suppression (SAS).
• Quantified SMKI cardiotoxicity using "FoldCmax" to relate drug concentrations to clinical exposure levels.

Main Results:

• Combined hPSC-CM based electrophysiological and non-electrophysiological assays demonstrated significantly higher predictive value for cardiotoxicity compared to individual assays.
• The combined assay approach outperformed the current FDA-recommended hERG assay in predicting SMKI-induced cardiotoxicity.
• Results provided mechanistic details on cardiomyocyte toxicities, aiding early risk assessment.

Conclusions:

• Combined hPSC-CM based electrophysiological and non-electrophysiological assays are superior for predicting SMKI-induced cardiotoxicity.
• These assays offer valuable mechanistic insights early in drug development, surpassing traditional methods.
• This approach can guide the development of safer and more cost-effective drugs by identifying cardiac liabilities sooner.