The evaluation of cardiovascular toxicity is a significant challenge in drug development. Preclinical evaluation of cardiovascular safety involves a multifaceted approach, encompassing a plethora of in vitro and in vivo endpoints.
These assessments continuously evolve, aiming to mitigate the incidence of cardiovascular toxicity that may emerge during clinical trials.
To shed light on the intricate dynamics of cardiovascular toxicity, let’s examine the case of two distinct small-molecule inhibitors described in a recent study1 by Yevgeniya E. Koshman et al.
Kinase inhibitors are widely used drugs, especially in oncology, due to their ability to target enzymatic sites crucial for cellular regulation. However, recent concerns have emerged regarding cardiovascular toxicity associated with small-molecule kinase inhibitors, with diverse observed cardiac events and mechanisms driving toxicity, independent of the intended pharmacologic target.
In this study the two kinase inhibitors consistently impacted cardiovascular function parameters in dogs. They were shown to cause cardiovascular toxicity, leading to myocardial degeneration and fibrosis in the left ventricular papillary muscle of the dogs.
Effects of each inhibitor on hemodynamic and electrocardiographic endpoints were assessed during a 2-week dose-range finding and a 4-week toxicity studies.
Notably, both inhibitors increased heart rate, left ventricular contractility and cardiac output, while decreasing mean arterial pressure. Cardiovascular degeneration/necrosis with and without fibrosis was observed in dogs and correlated to increases in serum cardiac troponin, a biomarker for assessing cardiac injury or toxicity (particularly in dogs where it has exhibited less variability compared to other species).
The pathology results correlated with elevated troponin levels and changes in hemodynamics. These findings underscored the intricate link between physiological responses and toxicological manifestations in cardiovascular safety assessment. The research conducted to assess the toxicologic effects on both cardiac function and morphology in vitro and in vivo, highlights the vital role of interdisciplinary collaboration in evaluating the cardiovascular safety profile of novel treatments.
By browsing this website, you accept the use of cookies for statistical purposes.
When you visit any web site, it may store or retrieve information on your browser, mostly in the form of cookies. Control your personal Cookie Services here.
