Objective:

To determine the cerebrospinal fluid (CSF) to plasma concentration ratio of ubrogepant in participants with a history of migraine.

Background:

Ubrogepant is an orally active CGRP receptor antagonist approved for the acute treatment of migraine in adults.

Design/Methods:

In a Phase 1b multi-center, open-label, study 8 male and female participants who had been diagnosed with migraine for at least 1 year were administered a single 100 mg dose of ubrogepant. Plasma and CSF concentrations of ubrogepant were determined using LC-MS/MS methods. Ubrogepant CSF/plasma concentration ratio at each time point for each participant was calculated. Descriptive statistics for the ubrogepant CSF/plasma ratio were calculated for each time point. The safety and tolerability profiles of ubrogepant were evaluated by clinical assessment of adverse events, physical examinations, 12-lead ECGs, laboratory tests (hematology, serum chemistry, and urinalysis), and vital sign measurements.

Results:

Mean(SD) plasma and CSF ubrogepant concentrations at 2 hours were 354(163) and 1.08(0.8) ng/mL, respectively and at 4 hours were 218(84) and 2.26(1.94) ng/mL, respectively.  The mean ubrogepant CSF/plasma concentration ratio was 0.36% at 2 hours post-dose and 0.94% at 4 hours post-dose. There were no serious adverse events, deaths, significant changes in clinical labs, vital signs, or ECGs.

Conclusions:

Ubrogepant concentrations in the CSF are approximately 1% of plasma concentrations at 4 hours post-dose. Based on the results of pharmacodynamic assessments of the inhibition of capsaicin-induced increases in forearm dermal blood flow suggesting ubrogepant EC₅₀ value of approximately 1.41 ng/mL, the CSF concentrations observed at 4 hours post-dose suggest that ubrogepant could act both centrally and peripherally to relieve migraine symptoms.