TY - JOUR
T1 - Mechanistic Investigations Support Liver Safety of Ubrogepant
AU - Smith, Brenda
AU - Rowe, Josh
AU - Watkins, Paul B.
AU - Ashina, Messoud
AU - Woodhead, Jeffrey L.
AU - Sistare, Frank D.
AU - Goadsby, Peter J.
PY - 2020/9/1
Y1 - 2020/9/1
N2 - 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.
AB - 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.
KW - calcitonin gene-related peptide receptor antagonist
KW - DILI
KW - DILIsym
KW - headache
KW - migraine
KW - quantitative systems toxicology
UR - http://www.scopus.com/inward/record.url?scp=85091127122&partnerID=8YFLogxK
U2 - 10.1093/toxsci/kfaa093
DO - 10.1093/toxsci/kfaa093
M3 - Article
C2 - 32579200
AN - SCOPUS:85091127122
SN - 1096-6080
VL - 177
SP - 84
EP - 93
JO - Toxicological sciences : an official journal of the Society of Toxicology
JF - Toxicological sciences : an official journal of the Society of Toxicology
IS - 1
ER -
