ArticleToxicological sciences : an official journal of the Society of Toxicology2022
Comparing the Liver Safety Profiles of 4 Next-Generation CGRP Receptor Antagonists to the Hepatotoxic CGRP Inhibitor Telcagepant Using Quantitative Systems Toxicology Modeling.
Article in Toxicological sciences : an official journal of the Society of Toxicology, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed, 46 citations in OpenAlex.
- In Silico Clinical Trials in Drug Development: Virtual Patients, Applications, and Regulatory Convergence.Clinical pharmacology and therapeutics · 2026Review
- Quantitative Systems Toxicology Model Predicts Obeticholic Acid-Associated Liver Injury in Metabolic Dysfunction-Associated Steatotic Liver Disease.Clinical pharmacology and therapeutics · 2026Article
- Retrospective analysis of the tolerability and effectiveness of rimegepant for the acute treatment of migraine in adolescents.Headache · 2026Article
- Quantitative Systems Toxicology Modeling with DILIsym to Support Phase 3 Dose Selection for Fezolinetant.Clinical pharmacology and therapeutics · 2026Article
- Review
- 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 in Primary Care: A Targeted Approach to Acute and Preventive Treatment of Migraine.Pain and therapy · 2025Review
- Adverse events associated with gepants: a pharmacovigilance analysis based on the FDA adverse event reporting system.The journal of headache and pain · 2025Article
- Modeling and Simulation of Acetaminophen Pharmacokinetics and Hepatic Biomarkers After Overdoses of Extended-Release and Immediate-Release Formulations in Healthy Adults Using the Quantitative Systems Toxicology Software Platform DILIsym.CPT: pharmacometrics & systems pharmacology · 2025Article
- Application of Mechanistic Mathematical Modeling to Toxicology: Quantitative Systems Toxicology (QST).Handbook of experimental pharmacology · 2025Review
- Gepants: targeting the CGRP pathway for migraine relief.Frontiers in pharmacology · 2025Review
- Comparison of gepant effects at therapeutic plasma concentrations: connecting pharmacodynamics and pharmacokinetics.The journal of headache and pain · 2024Article
- Review
- Blocking the CGRP Receptor: Differences across Human Vascular Beds.Pharmaceuticals (Basel, Switzerland) · 2023Article
- Molecular Mechanisms of Migraine: Nitric Oxide Synthase and Neuropeptides.International journal of molecular sciences · 2023Review
- Gepants for Acute and Preventive Migraine Treatment: A Narrative Review.Brain sciences · 2022Review
- Investigating bile acid-mediated cholestatic drug-induced liver injury using a mechanistic model of multidrug resistance protein 3 (MDR3) inhibition.Frontiers in pharmacology · 2022Article
- Article
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Authors and funding
5 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Calcitonin gene-related peptide (CGRP) signaling inhibitors have shown efficacy in both the acute and preventive treatment of migraine. Telcagepant, a first-generation CGRP receptor antagonist, was effective but failed in clinical trials due to hepatotoxicity. Subsequently, although 4 next-generation CGRP receptor antagonists (rimegepant, zavegepant, atogepant, and ubrogepant) were being advanced into late-stage clinical trials, due to telcagepant's failure, more confidence in the liver safety of these compounds was needed. DILIsym v6A, a quantitative systems toxicology (QST) model of drug-induced liver injury (DILI), was used to model all 5 compounds and thus to compare the 4 next-generation CGRP receptor antagonists to telcagepant. In vitro experiments were performed to measure the potential for each compound to inhibit bile acid transporters, produce oxidative stress, and cause mitochondrial dysfunction. Physiologically based pharmacokinetic models were produced for each compound in order to appropriately estimate liver exposure. DILIsym predicted clinical elevations of liver enzymes and bilirubin for telcagepant, correctly predicting the observed DILI liability of the first-generation compound. By contrast, DILIsym predicted that each of the 4 next-generation compounds would be significantly less likely to cause DILI than telcagepant. Subsequent clinical trials have validated these predictions for each of the 4 compounds, and all 3 of the compounds submitted to FDA to date (rimegepant, ubrogepant, and atogepant) have since been approved by the FDA with no warning for hepatotoxicity. This work demonstrates the potential for QST modeling to prospectively differentiate between hepatotoxic and nonhepatotoxic molecules within the same class.
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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.