Rimegepant
Rimegepant Uses, Dosage, Side Effects, Food Interaction and all others data.
Rimegepant is an oral antagonist of the CGRP receptor developed by Biohaven Pharmaceuticals. It received FDA approval on February 27, 2020 for the acute treatment migraine headache. While several parenteral antagonists of CGRP and its receptor have been approved for migraine therapy (e.g. erenumab, fremanezumab, galcanezumab), rimegepant and ubrogepant are the only members of the "gepants" family of medications remaining in development, and the only CGRP antagonists that possess oral bioavailability.
The current standard of migraine therapy involves abortive treatment with "triptans", such as sumatriptan, but these medications are contraindicated in patients with pre-existing cerebrovascular and cardiovascular disease due to their vasoconstrictive properties. Antagonism of the CGRP pathway has become an attractive target for migraine therapy as, unlike the triptans, oral CGRP antagonists have no observed vasoconstrictive properties and are therefore safer for use in patients with contraindications to standard therapy.
Rimegepant helps to abort migraine headaches by preventing the activity of a pronociceptive molecule that has been implicated in migraine pathophysiology. It is intended for use as an abortive migraine therapy and therefore has a relatively rapid onset of effect, with most efficacy trials evaluating for effect at the 2 hour mark.
| Trade Name | Rimegepant |
| Availability | Prescription only |
| Generic | Rimegepant |
| Rimegepant Other Names | Rimegepant |
| Related Drugs | Nurtec ODT, Zomig, Tosymra, Ubrelvy, Botox, propranolol, diclofenac, atenolol, topiramate, nifedipine |
| Type | |
| Formula | C28H28F2N6O3 |
| Weight | Average: 534.568 Monoisotopic: 534.219095112 |
| Protein binding | Rimegepant is approximately 96% plasma protein-bound. The specific proteins to which rimegepant binds have not been elucidated. |
| Groups | Approved, Investigational |
| Therapeutic Class | |
| Manufacturer | |
| Available Country | United States |
| Last Updated: | September 19, 2023 at 7:00 am |
Uses
Rimegepant is an oral CGRP receptor antagonist used for the acute treatment of migraines with or without aura in adults.
Rimegepant is indicated for the acute treatment of migraine with or without aura in adults.
Rimegepant is also used to associated treatment for these conditions: Migraine With Aura, Migraine Without Aura
How Rimegepant works
The currently accepted theory of migraine pathophysiology considers dysfunction of the central nervous system, in particular the trigeminal ganglion, to be the root cause behind the condition. Activation of the trigeminal ganglion triggers the stimulation of trigeminal afferents that project to the spinal cord and synapse on various pain-sensing intra- and extracranial structures, such as the dura mater. Pain signals are then further transmitted via second-order ascending neurons to the brainstem, hypothalamus, and thalamic nuclei, and from there to several cortical regions (e.g. auditory, visual, motor cortices). The trigeminal ganglion appears to amplify and perpetuate the migraine headache pain through the activation of perivascular fibers and the release of molecules involved in pain generation, such as calcitonin gene-related peptide (CGRP).
The α-isoform of CGRP, expressed in primary sensory neurons, is a potent vasodilator and has been implicated in migraine pathogenesis - CGRP levels are acutely elevated during migraine attacks, return to normal following treatment with triptan medications, and intravenous infusions of CGRP have been shown to trigger migraine-like headaches in migraine patients. In addition to its vasodilatory properties, CGRP appears to be a pronociceptive factor that modulates neuronal excitability to facilitate pain responses.
Rimegepant is an antagonist of the calcitonin gene-related peptide receptor - it competes with CGRP for occupancy at these receptors, preventing the actions of CGRP and its ability to amplify and perpetuate migraine headache pain, ultimately terminating the headache.
Toxicity
There is no specific antidote for rimegepant overdosage and clinical experience is limited. Treatment should consist of general supportive and symptomatic measures including monitoring of vital signs and general observation. Hemodialysis is unlikely to be of benefit given rimegepant's high serum protein binding.
Food Interaction
- Take with or without food. Pharmacokinetics may be altered when administered with high-fat meals, but the clinical relevance of these effects is unknown.
[Moderate] ADJUST DOSING INTERVAL: Coadministration with grapefruit or grapefruit juice may increase the plasma concentrations of rimegepant.
The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall induced by certain compounds present in grapefruit.
Concomitant administration of a single dose of rimegepant (75 mg) with itraconazole, a strong CYP450 3A4 inhibitor, at steady state increased the systemic exposure (AUC) and peak plasma concentration (Cmax) of rimegepant by 4-fold and approximately 1.5-fold, respectively.
The manufacturer also states that concomitant administration of rimegepant with a moderate CYP450 3A4 inhibitor may increase rimegepant AUC by less than 2-fold.
Because grapefruit juice inhibits primarily intestinal rather than hepatic CYP450 3A4, the magnitude of interaction is greatest for those drugs that undergo significant presystemic metabolism by CYP450 3A4 (i.e., drugs with low oral bioavailability).
In general, the effect of grapefruit juice is concentration-, dose- and preparation-dependent, and can vary widely among brands.
Certain preparations of grapefruit juice (e.g., high dose, double strength) have sometimes demonstrated potent inhibition of CYP450 3A4, while other preparations (e.g., low dose, single strength) have typically demonstrated moderate inhibition.
Pharmacokinetic interactions involving grapefruit juice are also subject to a high degree of interpatient variability, thus the extent to which a given patient may be affected is difficult to predict.
MONITOR: When administered with a high-fat meal under fed condition, Tmax was delayed by 1 hour, which resulted in a 42% to 53% reduction in Cmax and a 32% to 38% reduction in AUC.
However, the impact of this reduction on rimegepant efficacy remains unknown.
MANAGEMENT: Rimegepant may be administered with or without food.
Until more information is available, patients receiving rimegepant may want to avoid the regular consumption of grapefruits and grapefruit juice to prevent undue increases in plasma levels and systemic effects of rimegepant.
If grapefruit or grapefruit juice is consumed concomitantly with rimegepant, the manufacturer recommends avoiding another dose of rimegepant within 48 hours.
Rimegepant Drug Interaction
Unknown: aripiprazole, amphetamine / dextroamphetamine, erenumab, suvorexant, diphenhydramine, onabotulinumtoxinA, buspirone, docusate, duloxetine, acetaminophen / butalbital / caffeine, clonazepam, lurasidone, semaglutide, topiramate, ketorolac, cholecalciferol, lisdexamfetamine, ondansetron, sertraline, cetirizine
Rimegepant Disease Interaction
Volume of Distribution
At steady state, the volume of distribution is approximately 120 L.
Elimination Route
The absolute oral bioavailability of rimegepant is approximately 64%. Following oral administration of the orally disintegrating tablet, maximum plasma concentrations were achieved at 1.5 hours (Tmax).
When administered with a high-fat meal, Tmax is delayed by 1 hour, Cmax is decreased by 42-53%, and AUC is decreased by 32-38%. The clinical significance of this difference in pharmacokinetics is unknown.
Half Life
The elimination half-life in healthy subjects is approximately 11 hours.
Elimination Route
Following oral administration of radiolabeled rimegepant in healthy subjects, 78% of the administered radioactivity was recovered in feces and 24% in urine. Unchanged parent drug was the major component in each, comprising 42% and 51% of the recovered doses, respectively.
Innovators Monograph
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