Mechanistic Investigations Support Liver Safety of Ubrogepant.
Toxicol Sci
; 177(1): 84-93, 2020 09 01.
Article
en En
| MEDLINE
| ID: mdl-32579200
ABSTRACT
Small-molecule calcitonin gene-related peptide (CGRP) receptor antagonists have demonstrated therapeutic efficacy for the treatment of migraine. However, previously investigated CGRP receptor antagonists, telcagepant and MK-3207, were discontinued during clinical development because of concerns about drug-induced liver injury. A subsequent effort to identify novel CGRP receptor antagonists less likely to cause hepatotoxicity led to the development of ubrogepant. The selection of ubrogepant, following a series of mechanistic studies conducted with MK-3207 and telcagepant, was focused on key structural modifications suggesting that ubrogepant was less prone to forming reactive metabolites than previous compounds. The potential for each drug to cause liver toxicity was subsequently assessed using a quantitative systems toxicology approach (DILIsym) that incorporates quantitative assessments of mitochondrial dysfunction, disruption of bile acid homeostasis, and oxidative stress, along with estimates of dose-dependent drug exposure to and within liver cells. DILIsym successfully modeled liver toxicity for telcagepant and MK-3207 at the dosing regimens used in clinical trials. In contrast, DILIsym predicted no hepatotoxicity during treatment with ubrogepant, even at daily doses up to 1000 mg (10-fold higher than the approved clinical dose of 100 mg). These predictions are consistent with clinical trial experience showing that ubrogepant has lower potential to cause hepatotoxicity than has been observed with telcagepant and MK-3207.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Piridinas
/
Pirroles
/
Antagonistas del Receptor Peptídico Relacionado con el Gen de la Calcitonina
Tipo de estudio:
Prognostic_studies
Idioma:
En
Revista:
Toxicol Sci
Asunto de la revista:
TOXICOLOGIA
Año:
2020
Tipo del documento:
Article