title: A novel and integrated approach for the identification and characterization of drug-induced cardiac toxicity in the dog.
abstract: 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.
authors.affiliation: 1Safety Assessment Dept., GlaxoSmithKline Research Centre, Verona, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Casartelli
authors.forename: Anna
authors.initials: A
authors.lastname: Lanzoni
authors.forename: Rodolfo
authors.initials: R
authors.lastname: Comelli
authors.forename: Federica
authors.initials: F
authors.lastname: Crivellente
authors.forename: Rossella
authors.initials: R
authors.lastname: Defazio
authors.forename: Roberto
authors.initials: R
authors.lastname: Dorigatti
authors.forename: Nicola
authors.initials: N
authors.lastname: Fasdelli
authors.forename: Ivo
authors.initials: I
authors.lastname: Faustinelli
authors.forename: Sabrina
authors.initials: S
authors.lastname: Pagliarusco
authors.forename: Marcello
authors.initials: M
authors.lastname: Tontodonati
authors.forename: Patrizia
authors.initials: P
authors.lastname: Cristofori
mesh_terms: D000284:Administration, Oral; D000818:Animals; D015415:Biomarkers; D052279:Creatine Kinase, MB Form / Q000032:analysis; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D006331:Heart Diseases / Q000139:chemically induced* / Q000473:pathology; D008297:Male; D046529:Microscopy, Electron, Transmission; D023421:Models, Animal; D009206:Myocardium / Q000473:pathology / Q000648:ultrastructure; D020097:Natriuretic Peptide, Brain / Q000032:analysis; D064729:Neurokinin-1 Receptor Antagonists; D010446:Peptide Fragments / Q000032:analysis; D010879:Piperazines / Q000008:administration & dosage* / Q000633:toxicity*; D010880:Piperidines / Q000008:administration & dosage* / Q000633:toxicity*; D019210:Troponin I / Q000032:analysis; D014508:Urea
chemical_list: D015415:Biomarkers; D052279:Creatine Kinase, MB Form; D020097:Natriuretic Peptide, Brain; D064729:Neurokinin-1 Receptor Antagonists; D010446:Peptide Fragments; D010879:Piperazines; D010880:Piperidines; D019210:Troponin I; C109794:pro-brain natriuretic peptide (1-76); C531951:casopitant; D014508:Urea