Key result
Long-term oral administration of casopitant in dogs resulted in cardiac changes that were characterized using an integrated evaluation of cardiovascular parameters, electron microscopy, and biomarkers.
Why the study?
Does an integrated investigational approach identify early cardiotoxicity of long-term oral casopitant in dogs?
Does an integrated investigational approach identify early cardiotoxicity of long-term oral casopitant in dogs?
An integrated approach using biomarkers and imaging can identify early drug-induced cardiotoxicity in preclinical models, aiding drug development decisions.
Novel insights into late CV toxicity detection; hypothesis-generating for refined chronic drug safety paradigms.
Cardiovascular toxicity represents one of the major reasons for the termination of the development of drugs, even in late development phases. This growing issue is often not restricted to specific therapeutic areas, and it is gaining critical importance, in particular for chronically administered drugs, highlighting the limitations in terms of sensitivity of the current investigational paradigms. Furthermore, drug-related changes may become evident after long-term administration for different reasons, including accumulation of the drug in the heart. This article describes how the integrated use of investigational tools represents a powerful approach for the early identification and characterization of cardiotoxicity in preclinical development. Cardiac changes were observed in the dog after long-term oral administration of casopitant, a neurokinin 1 receptor antagonist, developed for the treatment of depression and anxiety. Different approaches and sensitive biomarkers were used in a time-course study to investigate the onset, progression, and reversibility of the lesion. The integrated evaluation of cardiovascular parameters, electron microscopy, troponin I, and natriuretic peptide results highlighted any minimal early changes, allowing the full and deep characterization of the lesion. The outcome of this study was the driver for drug development decision making on casopitant and backup drugs.
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Casartelli et al. (2010) studied Drug-induced cardiac toxicity. Casopitant was evaluated on Cardiac changes / cardiotoxicity. Long-term oral administration of casopitant in dogs resulted in cardiac changes that were characterized using an integrated evaluation of cardiovascular parameters, electron microscopy, and biomarkers.
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