Ubrogepant

Breast Feeding; Lactation; Milk, Human; Analgesics; Calcitonin Gene Related Peptide Receptor Antagonists; CGRP-R Inhibitors

FDA approved drugs -> Active ingredient

FDA approved drugs -> Active ingredient

In preregistration controlled trials of ubrogepant 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 prompt stopping of therapy. Similar episodes have not been reported with ubrogepant.

Drug Induced Liver Injury Rank (DILIrank 2.0)

Ubrogepant

vNo-DILI-concern

0

No match

DOI:10.1016/j.drudis.2016.02.015

N - Nervous system

QN - Nervous system

Ubrogepant 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.

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. Ubrogepant 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.