Ubrogepantum
Ubrogepantum Uses, Dosage, Side Effects, Food Interaction and all others data.
Ubrogepantum is indicated for the acute treatment of migraine headaches with or without aura in adults. It was approved by the FDA on December 23, 2019, and is the first oral calcitonin gene-related peptide (CGRP) receptor antagonist approved for the acute treatment of migraine. Several oral small molecule CGRP receptor antagonists, belonging to a class of medications referred to as "gepants", have been investigated for migraines, but only ubrogepant and rimegepant remain in clinical development. Previous agents within this class were efficacious but limited by liver toxicity - this led to the development of ubrogepant, which was designed to be a hepatoxicity-free alternative to its predecessors. Several parenteral monoclonal antibodies acting against the CGRP pathway (e.g. erenumab, fremanezumab, galcanezumab) have also been approved in recent years.
Compared to the current standard of therapy for migraine treatment, namely triptans such as sumatriptan and almotriptan, CGRP antagonists present several advantages. They appear to be better tolerated, do not contribute to medication overuse headaches, and carry no apparent cardiovascular risk, making them suitable for use in patients with cardiovascular disease. The development of oral gepants, including ubrogepant, may therefore constitute a significant advance in migraine headache treatment and may become the new standard of therapy in the treatment of this debilitating condition.
Ubrogepantum acutely treats migraine headache pain by blocking the activity of a key transmitter involved in migraine pathogenesis. Exposure to ubrogepant can be significantly increased in patients with severe hepatic or renal insufficiency - dose adjustments are required for these patients in order to avoid excessive exposure, and ubrogepant is not recommended in patients with end-stage renal disease.
| Trade Name | Ubrogepantum |
| Availability | Prescription only |
| Generic | Ubrogepant |
| Ubrogepant Other Names | Ubrogepant, Ubrogépant, Ubrogepantum |
| Related Drugs | Ubrelvy, Botox, diclofenac, celecoxib, metoclopramide, sumatriptan, Imitrex, Reglan |
| Type | |
| Formula | C29H26F3N5O3 |
| Weight | Average: 549.554 Monoisotopic: 549.198774206 |
| Protein binding | Ubrogepant is 87% protein-bound in vitro, although the specific proteins to which ubrogepant binds have not been elucidated. |
| Groups | Approved, Investigational |
| Therapeutic Class | |
| Manufacturer | |
| Available Country | |
| Last Updated: | September 19, 2023 at 7:00 am |
Uses
Ubrogepantum is an oral CGRP antagonist used in the acute treatment of migraine with or without aura.
Ubrogepantum is indicated for the acute treatment of migraine with or without aura in adults.
Ubrogepantum is also used to associated treatment for these conditions: Migraine With Aura, Migraine Without Aura
How Ubrogepantum 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.
Ubrogepantum is a potent 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
As clinical experience with ubrogepant is limited, detailed toxicity information is not readily available. Prescribing information for ubrogepant recommends a monitoring period of at least 24 hours following overdose based on its 5 to 7 hour half-life.
Food Interaction
- Avoid St. John's Wort. This herb induces CYP3A metabolism and may reduce serum levels of ubrogepant.
- Take with or without food. Co-administration with food slightly alters pharmacokinetics, but not to a clinically significant extent.
[Moderate] ADJUST DOSE: Grapefruit and grapefruit juice may increase the plasma concentrations of ubrogepant.
The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit.
Inhibition of hepatic CYP450 3A4 may also contribute.
The interaction has not been studied with grapefruit but has been reported for other CYP450 3A4 inhibitors.
When ubrogepant was administered with the moderate CYP450 3A4 inhibitor verapamil during in vivo studies, ubrogepant peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 2.8- and 3.5-fold, respectively.
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.
When administered with a high-fat meal, ubrogepant time to maximum plasma concentration (Tmax) was delayed by 2 hours, which resulted in a 22% decrease in Cmax and no change in AUC.
Ubrogepantum was administered without regard to food in clinical efficacy studies.
MANAGEMENT: Ubrogepantum may be administered with or without food.
Per the manufacturer, when coadministered with grapefruit or grapefruit juice, the initial ubrogepant dose should be 50 mg, and if needed, a second ubrogepant dose should be avoided within 24 hours of the initial dose.
Ubrogepantum Drug Interaction
Unknown: erenumab, fremanezumab, contained in alcoholic beverages , naproxen, zolpidem, ocular lubricant ophthalmic, diphenhydramine, buspirone, duloxetine, frovatriptan, sumatriptan, pregabalin, rimegepant, vortioxetine, acetaminophen, cyanocobalamin, ascorbic acid, cholecalciferol, ondansetron, sertraline
Ubrogepantum Disease Interaction
Volume of Distribution
The apparent central volume of distribution following oral administration is approximately 350 L.
Elimination Route
Following oral administration, Tmax occurs between 0.7 and 1.5 h. When administered with a high-fat meal, Tmax is delayed by approximately 2 hours and Cmax was reduced by 22% with no significant changes to the AUC. Ubrogepantum exhibits dose-proportional pharmacokinetics throughout the entirety of its recommended dosing range.
Half Life
Ubrogepantum has an elimination half-life of 5-7 hours.
Clearance
The apparent oral clearance of ubrogepant is approximately 87 L/h.
Elimination Route
The main route of elimination is fecal/biliary, while renal excretion is comparatively minor - following administration of a single oral dose to healthy subjects, approximately 42% of the dose was recovered unchanged in the feces and 6% was recovered unchanged in the urine.
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