Mechanism of Action of Ubrelvy (Ubrogepant)
Ubrelvy (ubrogepant) is a small-molecule calcitonin gene-related peptide (CGRP) receptor antagonist that competitively blocks the CGRP receptor-binding site after CGRP has been released during a migraine attack, preventing the peptide from activating the receptor and thereby interrupting the trigeminal nerve pain and inflammation pathway central to migraine pathophysiology. 1
Pharmacological Mechanism
Ubrogepant functions by directly occupying the CGRP receptor-binding site, competitively preventing CGRP from binding to and activating its receptor. 1, 2
The drug exhibits high binding affinity for the human CGRP receptor (Ki = 0.070 nM) and potently blocks human α-CGRP-stimulated cAMP response with an IC50 of 0.08 nM. 2
Ubrogepant demonstrates highly selective antagonist activity for the CGRP receptor compared with other members of the human calcitonin receptor family, ensuring specificity of action. 2
Distinction from Other Migraine Therapies
Unlike CGRP monoclonal antibodies (such as fremanezumab, galcanezumab, or eptinezumab), which bind to the CGRP peptide itself to neutralize it, ubrogepant directly occupies the receptor-binding site on the CGRP receptor. 1, 3
Ubrogepant works exclusively through CGRP receptor antagonism without any serotonergic activity, which is clinically significant because its mechanism is believed to be nonvasoconstrictive, potentially carrying lower cardiovascular risks than vasoactive medications like triptans in patients with cardiovascular risk factors. 1
Unlike triptans, which bind to 5-HT1B and 5-HT1D serotonin receptors and cause vasoconstriction, ubrogepant provides a distinct therapeutic approach through pure CGRP receptor antagonism. 4
Unlike ditans (such as lasmiditan), which block CGRP release by binding to 5-HT1F receptors, ubrogepant directly blocks the CGRP receptor after the peptide has already been released. 4
Clinical Pharmacodynamics
In vivo studies using a pharmacodynamic model of capsaicin-induced dermal vasodilation (CIDV) in both rhesus monkeys and humans demonstrated that ubrogepant produced concentration-dependent inhibition of CIDV with a mean EC50 of 2.6 nM in humans, indicating a predictable pharmacokinetic-pharmacodynamic relationship. 2
The FDA-approved indication for ubrogepant is for acute treatment of migraine (± aura) in adults, with the VA/DoD guidelines providing a "weak for" recommendation for short-term treatment of migraine. 5, 6