ArticleToxicological sciences : an official journal of the Society of Toxicology2020
Mechanistic Investigations Support Liver Safety of Ubrogepant.
Article in Toxicological sciences : an official journal of the Society of Toxicology, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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The trial behind it
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Who cites it
14 citing papers in PubMed, 27 citations in OpenAlex.
- Atogepant Is Not Associated With Clinically Meaningful Alanine Aminotransferase Elevations in Healthy Adults.Clinical and translational science · 2021Trial
- In-Vitro Generation of T-Cell Clones to Difluorophenylglyoxal: Implications for Understanding the Immunogenicity of MK-3207.Chemical research in toxicology · 2026Article
- Quantitative Systems Toxicology Modeling with DILIsym to Support Phase 3 Dose Selection for Fezolinetant.Clinical pharmacology and therapeutics · 2026Article
- Quantitative systems toxicology: modelling to mechanistically understand and predict drug safety.Nature reviews. Drug discovery · 2026Review
- Quantitative Systems Toxicology Predicts Ivacaftor-Induced Oxidative Stress Contributes to CFTR Modulator Hepatotoxicity.Clinical pharmacology and therapeutics · 2026Article
- Gepants: Key Features of A Potent Therapeutic Option and Considerations in The Latin American Context.Revista de neurologia · 2025Review
- The UK's Early Access to Medicines Scheme 10 years on: an evaluation using publicly available data.JRSM open · 2025Article
- Application of Mechanistic Mathematical Modeling to Toxicology: Quantitative Systems Toxicology (QST).Handbook of experimental pharmacology · 2025Review
- Development of a Novel In Silico Classification Model to Assess Reactive Metabolite Formation in the Cysteine Trapping Assay and Investigation of Important Substructures.Biomolecules · 2024Article
- The Combination of a Human Biomimetic Liver Microphysiology System with BIOLOGXsym, a Quantitative Systems Toxicology (QST) Modeling Platform for Macromolecules, Provides Mechanistic Understanding of Tocilizumab- and GGF2-Induced Liver Injury.International journal of molecular sciences · 2023Article
- Review
- New Generation Gepants: Migraine Acute and Preventive Medications.Journal of clinical medicine · 2022Review
- Review
- Article
Corrections and comments
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Authors and funding
7 authors at 5 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.