Indications
Atogepant is approved for the preventive treatment of migraines in adults by leading health authorities, including the FDA, EMA, and Health Canada. This medication specifically targets the reduction of migraine frequency and severity in individuals who experience recurring migraine episodes.
Pharmacodynamics
Atogepant functions by antagonizing calcitonin gene-related peptide (CGRP), a pronociceptive molecule implicated in the pathophysiology of migraines. By blocking CGRP activity, atogepant reduces the occurrence of migraines. It is intended for preventive use and is administered once daily. No dose adjustment is required for patients with mild to moderate hepatic or renal impairment. However, atogepant should be avoided in patients with severe hepatic impairment, and those with severe renal impairment should limit their dosage to a maximum of 10 mg per day.
Absorption
Following oral administration, atogepant reaches peak plasma concentration within approximately 2 to 3 hours. The pharmacokinetics of atogepant are dose-proportional up to thrice the recommended maximum dosage. The presence of food does not significantly affect the absorption of the drug, ensuring consistent efficacy regardless of meal timing.
Metabolism
Atogepant is primarily metabolized via the cytochrome P450 enzyme CYP3A4. In human plasma, the predominant compounds are the parent drug and a glucuronide conjugate metabolite known as M23, comprising roughly 75% and 15% of the administered dose, respectively. Additionally, at least ten other metabolites are found in feces, each representing less than 10% of the administered dose.
Mechanism of Action
According to the prevailing theory of migraine pathophysiology, the dysfunction of the central nervous system, particularly the trigeminal ganglion, is considered the underlying cause of migraines. This condition arises when the activation of the trigeminal ganglion stimulates trigeminal afferents projecting to the spinal cord. These afferents then synapse on various intracranial and extracranial pain-sensitive structures, such as the dura mater. From there, pain signals are transmitted by second-order ascending neurons to the brainstem, hypothalamus, and thalamic nuclei, eventually reaching several cortical regions, including the auditory, visual, and motor cortices. The trigeminal ganglion plays a critical role in amplifying and perpetuating migraine headache pain by activating perivascular fibers and releasing pain-associated molecules like calcitonin gene-related peptide (CGRP). The α-isoform of CGRP, found in primary sensory neurons, is a powerful vasodilator implicated in migraine pathogenesis. CGRP levels significantly increase during migraine attacks and normalize after treatment with triptans, while its intravenous infusion can trigger migraine-like headaches in sufferers. Besides its vasodilatory effects, CGRP acts as a pronociceptive agent, modulating neuronal excitability to enhance pain responses. Atogepant functions as an antagonist of the CGRP receptor, effectively competing with CGRP for receptor binding, thereby inhibiting the peptide's actions and its role in initiating and sustaining migraine headache pain.
