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.
The authors propose that clinical ex vivo protein-binding studies should be performed on highly bound compounds (a definition of highly bound is suggested as > 95%). They also propose that in vitro studies, to measure the free drug, should be performed in whole blood, rather than in plasma, particularly if binding to proteins or blood cells is nonlinear.
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Casopitant is an NK-1 receptor antagonist which has been evaluated for the prevention of chemotherapy-induced and post-operative nausea and vomiting.• Data from in vitro systems suggested that casopitant both inhibits and induces CYP3A. Therefore, a risk of an interaction between casopitant and CYP3A4 substrates is likely.
WHAT THIS STUDY ADDS• Casopitant showed a dose and time dependent interaction with CYP3A, resulting in weak inhibition after a single dose, and weak to moderate inhibition after repeated dose administration.• The interaction with nifedipine could be predicted from the midazolam data for acute casopitant administration, but not after 14 days repeated dose casopitant administration, suggesting an induction effect complicating the interaction with nifedipine.• These results suggest that the use of in vitro or in vivo data to predict the interaction potential of other concomitant medications needs to account properly for any potential induction effect.
AIMTo evaluate the impact of single and repeated doses casopitant on the pharmacokinetics of single dose midazolam and nifedipine (CYP3A substrates) in healthy subjects. The effect on debrisoquine metabolism (CYP2D6 substrate) was also assessed.
The authors advocate directing more attention and efforts toward investigating tissue distribution: this approach might reduce late stage attrition. When unexpected tissue toxicity is found, measuring drug concentrations in the target tissue and characterising and measuring tissue metabolites could bring relevant information for interpreting the adverse finding. Evidence of slow accumulation of a long lasting metabolite in a tissue should be considered as an alert: this evidence can be obtained during short-term toxicity studies.
species: the maximum plasma concentration of radioactivity was generally observed 0.5 to 2 h after a single oral dose. In dog and female rat, as observed for humans, the principal circulating radiolabeled components were unchanged casopitant and its hydroxylated derivative M13. In rats, there was an evident sex-related difference in the rate of elimination of drug-related material with elimination being more rapid in males than in females. In dogs and mice, no notable sex differences were observed in the pattern of excretion. The elimination of drug-related radioactivity was largely by metabolism, with metabolites excreted primarily in the feces. The predominant route of metabolism was the oxidation of the parent molecule, observed together with loss of the Nacetyl group, N-demethylation, and modification of piperazine with consequent opening and cleavage of the ring, giving a complex pattern of metabolites. Conjugation of some of those oxidized products with glucuronic acid was observed. Urinary excretion in all three species was a minor route of elimination, accounting for between 2 and 7% of the dose, with unchanged parent drug never quantifiable.
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