Gepants overcome prior limitations, offer flexible acute and preventive migraine treatment with favorable safety

Migraine is a highly disabling neurological disorder, often characterized by frequent headache days. While various preventive therapies exist, conventional treatments are frequently limited by suboptimal efficacy or side effects like vasoconstriction, posing risks for patients with cardiovascular comorbidities. The calcitonin gene-related peptide (CGRP) pathway is a central mediator in migraine pathophysiology. Gepants, as novel CGRP receptor antagonists, offer a targeted approach, addressing the need for effective, safe, and flexible treatment options.

This scoping review followed PRISMA-ScR recommendations to synthesize evidence on gepant pharmacology, clinical applications, safety, and combination strategies. Researchers conducted a comprehensive search of PubMed/MEDLINE and Scopus from inception to July 2025, with an additional search in January 2026 for real-world studies. Data were extracted and summarized narratively, without quantitative synthesis, to provide a broad overview of the current landscape of gepant research and clinical use.

Second- and third-generation gepants, specifically ubrogepant, rimegepant, atogepant, and zavegepant, have successfully overcome the hepatotoxicity and bioavailability limitations observed with earlier compounds. Their pharmacokinetic properties enable flexible use for both acute and preventive migraine management. A significant finding is their lack of vasoconstrictive activity, making them a suitable option for patients with pre-existing cardiovascular comorbidities. Most gepants are primarily metabolized by cytochrome 3A4 (CYP3A4) and act as substrates for efflux transporters, requiring awareness of potential drug-drug interactions, though no clinically significant interactions with common migraine preventive medications have been reported. Preclinical and preliminary clinical evidence suggests:

Gepants have a low likelihood of inducing medication-overuse headache, a common concern with other acute migraine treatments. Furthermore, combination therapy with other migraine treatments appears mechanistically plausible and is supported by early pharmacokinetic and safety data, expanding future treatment possibilities.