Population Pharmacokinetics and Exposure-Response Analyses for Ubrogepant Efficacy and Safety in the Acute Treatment of Migraine: Analysis of Phase 1-3 Studies.

A population pharmacokinetic (popPK) model was developed for ubrogepant using data from 10 Phase 1, 1 Phase 2, and 2 Phase 3 studies. The data were described by a 2-compartment model with linear elimination and transit compartment absorption. Formulation, food intake, race, gender, and hepatic impairment had a statistically significant impact on ubrogepant PK. Significant exposure-response relationships were found for 2 h pain relief and pain freedom, and 24 h sustained pain relief and sustained pain freedom. Ubrogepant significantly improved the symptoms of phonophobia and photophobia, and the most bothersome migraine symptom, with a modest trend with ubrogepant dose. A Phase 3 study evaluating ubrogepant use during the prodrome was incorporated into the popPK model, and the mean transit time and inter-individual variability were re-estimated. Exposure-response analysis across multiple endpoints in the prodrome study (including absence of moderate/severe headache within 24 or 48 h, absence of headache of any intensity within 24 h, and ability to function normally within 24 h) showed a treatment effect with improved outcomes after receiving ubrogepant.