Rimegepant

534.5571264

534.56

997WVV895X

DTXSID70156003

114

2.3

1.45±0.1 g/cm3(Predicted)

Slightly soluble

|Warning|H361 (100%): Suspected of damaging fertility or the unborn child [Warning Reproductive toxicity]|P201, P202, P260, P281, P308+P313, P314, P405, and P501|The GHS information provided by 1 company from 1 notification to the ECHA C&L Inventory.

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.

In preregistration controlled trials of rimegepant in several thousand patients, mild-to-moderate serum aminotransferase elevations arose in a small percentage of patients (1% to 2%) and overall rates were not different from those in placebo recipients. In the controlled trials and subsequently with general use, there have been no reports of clinically apparent liver injury attributed to ubrogepant. In contrast, telcagepant, the initial oral CGRP receptor antagonist evaluated as therapy for migraine headaches, was abandoned during development because of several instances of clinically apparent liver injury in recipients that was characterized by marked elevations in serum aminotransferase levels and symptoms of fatigue, nausea and abdominal discomfort arising within 2 to 4 weeks of starting therapy which rapidly resolved with stopping therapy. Similar episodes have not been reported with rimegepant.

Rimegepant is approximately 96% plasma protein-bound. The specific proteins to which rimegepant binds have not been elucidated.

Rimegepant is indicated for the acute treatment of migraine with or without aura in adults.|Prevention of migraine headaches|Treatment of migraine headaches

Rimegepant is a small molecule inhibitor of the calcitonin gene-related peptide (CGRP) receptor that blocks the action of CGRP, a potent vasodilator believed to play a role in migraine headaches. Rimegepant is approved for treatment of acute migraine attacks. In clinical trials, rimegepant was generally well tolerated with only rare instances of transient serum aminotransferase elevations during therapy and with no reported instances of clinically apparent liver injury.

Migraine Headache Agents

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. Rimegepant does not require dose adjustment in patients with mild, moderate, or severe renal impairment, nor does it require dose adjustment in patients with mild or moderate hepatic impairment. In clinical trials, plasma concentrations of rimegepant were significantly higher in patients with severe (i.e. Child-Pugh C) hepatic impairment - it should therefore be avoided in this population. Hypersensitivity reactions have occurred during clinical studies and patients should be made aware of this possibility. Rimegepant should be discontinued immediately if hypersensitivity reaction occurs.

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 (T_max). When administered with a high-fat meal, T_max is delayed by 1 hour, C_max is decreased by 42-53%, and AUC is decreased by 32-38%. The clinical significance of this difference in pharmacokinetics is unknown.|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.|At steady state, the volume of distribution is approximately 120 L.

Rimegepant is metabolized by CYP3A4 and, to a lesser extent, CYP2C9. Specific metabolites of rimegepant have not been characterized and no major metabolites have been detected in plasma. Approximately 77% of an administered dose is eliminated unchanged, suggesting metabolism is likely to be a minor means of drug elimination.

The elimination half-life in healthy subjects is approximately 11 hours.

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.

(5S,6S,9R)-5-amino-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta(b)pyridin-9-yl 4-(2-oxo-2,3-dihydro-1H-imidazo(4,5-b)pyridin-1-yl)piperidine-1-carboxylate

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