Pre-clinical detection of mitochondrial toxicity in drug development

Abstract

Mitochondria play an essential role in myocardial tissue homeostasis and deterioration in mitochondrial function resulting from “off target” effects of drug exposure can lead to cardiomyocyte and endothelial cell death and as a consequence cardiovascular dysfunction.  This unpredicted cardiotoxicity is one of the causes of high rates of attrition during drug development, and poses and enormous financial burden on the pharmaceutical industry.  For example, a number of tyrosine kinase inhibitors (TKIs), have revealed previously unknown cardiotoxicity in the later clinical phases of drug development or after their regulatory approval. Assays that able to accurately predict mitochondrial toxicity are therefore urgently required. We have compared and evaluated a number of assays to assess mitochondrial toxicity following exposure to the TKI Mubritinib; a HER2 TKI that failed clinical safety and tolerability trials.  Our data have confirmed its mechanism of toxicity and we show that this drug acts as an inhibitor of the electron transport chain. In general, our data demonstrate that simple cellular assays are able to provide an accurate prediction of toxicity as well as more sophisticated assays e.g. those which employ the use of human-stem cell derived cardiomyocytes.