Migraine Attack Begins
Trigeminal CGRP release triggers the pain cascade of migraine.
- CLR+RAMP1: CGRP receptor (GPCR complex)
- 37 aa: Peptide size (CGRP neuropeptide)
- Minutes: Pain onset (trigeminal activation)
- 1 in 7: Migraine prevalence (people worldwide)
Trigeminovascular activation
Trigeminal nerve fibers release CGRP around meningeal blood vessels.
CGRP receptor structure
Receptor pairs calcitonin receptor-like receptor with RAMP1 accessory protein.
Pain amplification
CGRP binding triggers vasodilation and sensitizes pain-signaling neurons.
Oral Gepant Taken
A fast-dissolving tablet begins the absorption journey in the gut.
- ODT/oral: Tablet form (rimegepant, ubrogepant)
- ~64%: Oral bioavailability (rimegepant)
- 75 mg: Dose (standard) (rimegepant tablet)
- 2019–2020: Approval (FDA acute use)
Oral tablet formulation
Rimegepant and ubrogepant ship as fast-dissolving oral tablets.
Swallowing and disintegration
Tablet dissolves in stomach fluid within a few minutes.
GI absorption begins
Dissolved drug crosses gut lining into the portal bloodstream.
Rapid Absorption
The small molecule reaches peak plasma levels within roughly ninety minutes.
- ~1.5 h: Time to Tmax (median peak plasma)
- ~600 Da: Molecular weight (small molecule)
- ~11 h: Half-life (rimegepant)
- ~15 min: First detectable (post-dose)
First-pass metabolism
Liver processes some drug before it reaches systemic circulation.
Peak plasma concentration
Concentration peaks roughly ninety minutes after the dose.
Distribution to tissues
Gepant molecules diffuse from blood into neural tissue sites.
Receptor Antagonism
The compact gepant molecule wedges into the CGRP receptor pocket.
- Competitive: Binding mode (reversible antagonist)
- Sub-nM: Receptor affinity (high potency)
- >90%: CGRP blocked (at peak occupancy)
- None: Vasoconstriction (unlike triptans)
Competitive antagonism
Small gepant molecules occupy the receptor pocket CGRP needs.
Blocking the larger peptide
Bulkier CGRP peptide can no longer dock at the site.
Reversible, high-affinity binding
Antagonist unbinds slowly, sustaining blockade between doses.
Pain Relief
Blocked CGRP signaling lets migraine symptoms resolve without vasoconstriction.
- ~20%: Pain freedom (2h) (vs ~7% placebo)
- ~60%: Sustained relief (2–48h rimegepant)
- QOD dosing: Preventive use (rimegepant every other day)
- Minimal: Cardiovascular risk (no vasoconstriction)
Signaling cascade halted
Blocked receptors stop downstream vasodilation and pain signaling.
Symptom resolution
Headache, nausea, and light sensitivity gradually subside.
Dual-use therapy
Same drug treats acute attacks and prevents future ones.