Ubrogepant Plasma and Cerebrospinal Fluid Exposures in Participants With a History of Migraine: Findings From a Phase 1b Open‐Label Trial

Ubrogepant (Ubrelvy), a CGRP receptor antagonist, is approved for acute treatment of migraine with or without aura in adults. Because ubrogepant treats a neurological condition, it is of interest to know central nervous system exposure. Ubrogepant concentrations in plasma and cerebrospinal fluid (CSF) were measured in participants with a history of migraine. This analysis included a subset of participants with a ≥ 1 year history of migraine who were enrolled in a Phase 1b multi-center, open-label trial and who underwent a single CSF collection via lumbar puncture. All participants received a single oral dose of 100 mg ubrogepant. Plasma and CSF ubrogepant concentrations were measured using LC-MS/MS at pre-defined post-dose timepoints (plasma: 0-24 h; CSF: 2 or 4 h). Ubrogepant CSF/plasma concentration ratios at 2 and 4 h were determined. Ubrogepant safety and tolerability were evaluated through reporting of treatment-emergent adverse events (TEAEs; ≤ 30-days after dosing), physical examination, ECG, laboratory testing, and vital sign monitoring. A total of 8 participants were included. Mean (±SD) age was 34.5 ± 9.58 years and 4 participants (50%) were male. At 2 h, mean (±SD) CSF and plasma ubrogepant concentrations were 1.1 ± 0.8 and 354 ± 163 ng/mL, respectively (CSF/plasma ratio: 0.36% ± 0.29%); at 4 h, 2.3 ± 1.9 and 218 ± 84 ng/mL, respectively (CSF/plasma ratio: 0.94% ± 0.64%). No serious TEAEs, deaths, or significant changes in laboratory values, vital signs, or ECGs occurred. Because ubrogepant half maximal effective concentration (EC50) has been estimated at ~1.4 ng/mL, ubrogepant could act both centrally and peripherally to relieve migraine symptoms. ClinicalTrials.gov, NCT04179474 (registration date: 27 November 2019).