Ubrogepant

Dodick DW, et al. The Lancet, 2023, 402, 2307-2316.

This phase 3, multicentre, randomised, double-blind, placebo-controlled, crossover trial rigorously evaluated ubrogepant 100 mg for the acute treatment of migraine when administered during the prodrome phase. Conducted across 75 research centres and headache clinics in the USA, 518 participants aged 18-75 years with a history of migraine were enrolled. Each participant received either placebo or ubrogepant 100 mg for two successive qualifying prodrome events in a crossover design. Randomisation was managed by an automated web-response system employing permuted blocks of four, ensuring methodological robustness. At the onset of each qualifying prodrome event, participants ingested two oral tablets of the study drug, and headache severity was assessed within 24 h post-treatment. The primary endpoint-absence of moderate or severe headache within 24 h-was evaluated in the modified intention-to-treat population. Results demonstrated that ubrogepant significantly reduced the incidence of moderate or severe headache compared to placebo (46% vs. 29%; OR = 2.09; p < 0.0001). Adverse events within 48 h of administration were slightly higher with ubrogepant (17% vs. 12%). This study highlights the robust clinical application of ubrogepant 100 mg during the prodrome phase, confirming its efficacy and tolerability in preventing the progression of migraine attacks.

Eric M, et al. The Journal of Pharmacology and Experimental Therapeutics, 2020, 373(1), 160-166.

This case study focuses on the pharmacologic characterization of ubrogepant, with particular attention to its experimental validation. Ligand-binding assays were employed to determine ubrogepant's high affinity for human CGRP receptors, yielding a Ki value of 0.070 nM in cloned human receptors. These assays confirmed ubrogepant's selectivity, showing substantially lower affinities for non-human CGRP receptors. Functional cAMP response assays further highlighted ubrogepant's potent antagonist activity, with an IC50 of 0.08 nM in human α-CGRP-stimulated cAMP accumulation. The in vivo CGRP receptor antagonist activity was rigorously assessed in capsaicin-induced dermal vasodilation (CIDV) models in rhesus monkeys and humans, which revealed a concentration-dependent inhibition with mean EC50 values of 3.2 and 2.6 nM, respectively. Notably, brain penetration studies in monkeys indicated a cerebrospinal fluid:plasma ratio of 0.03, consistent with low central nervous system occupancy.