Indications
Rimegepant is prescribed for the acute treatment of migraine with or without aura in adults. It is also approved for the prevention of episodic migraine in the adult population.
Pharmacodynamics
Rimegepant functions by inhibiting the action of a pronociceptive molecule that plays a significant role in migraine pathophysiology. As an abortive migraine therapy, it exhibits a rapid onset of action, with efficacy typically assessed at the two-hour mark in clinical trials. The medication does not require dosage adjustments for patients with mild to severe renal impairment or for those with mild to moderate hepatic impairment. However, higher plasma concentrations have been observed in patients with severe hepatic impairment (Child-Pugh C), and its use is not recommended in this group. Additionally, hypersensitivity reactions have been reported; thus, patients should be informed of this risk, and the drug should be discontinued immediately if such a reaction occurs.
Absorption
Rimegepant displays an oral bioavailability of approximately 64%. When the orally disintegrating tablet is taken, maximum plasma concentrations (Tmax) are reached at approximately 1.5 hours. If consumed with a high-fat meal, Tmax is delayed by one hour, peak plasma concentration (Cmax) is reduced by 42-53%, and area under the curve (AUC) is decreased by 32-38%. The clinical significance of these pharmacokinetic changes remains unclear.
Metabolism
Rimegepant is predominantly metabolized by the CYP3A4 enzyme, with CYP2C9 also contributing to a lesser extent. While specific metabolites have not been identified, and no major metabolites have been detected in plasma, approximately 77% of the drug is excreted unchanged. This suggests that metabolism plays a minor role in the drug's elimination process.
Mechanism of Action
Rimegepant functions by targeting the calcitonin gene-related peptide (CGRP) receptor, acting as an antagonist. This mechanism is significant in addressing migraines, which are thought to primarily originate from central nervous system dysfunction, particularly within the trigeminal ganglion. The activation of the trigeminal ganglion initiates a cascade where trigeminal afferents project to the spinal cord and synapse on various pain-sensitive intra- and extracranial structures, including the dura mater. Subsequently, pain signals are conveyed through second-order ascending neurons to the brainstem, hypothalamus, thalamic nuclei, and several cortical regions, such as the auditory, visual, and motor cortices, thereby amplifying and perpetuating migraine headache pain through the activation of perivascular fibers. CGRP is a key molecule in this process, as its α-isoform, expressed in primary sensory neurons, is a notable vasodilator implicated in migraine pathogenesis. Elevated levels of CGRP are observed during migraine episodes and have been shown to decrease following treatment with triptan medications. Additionally, intravenous infusions of CGRP can trigger migraine-like headaches in individuals susceptible to migraines. By competing with CGRP for receptor occupancy, Rimegepant effectively inhibits the peptide's actions, thereby preventing the exacerbation of migraine pain and facilitating the resolution of headache symptoms.
