Phase Ib, open‐label, fixed‐sequence, drug–drug interaction, safety, and tolerability study between atogepant and ubrogepant in participants with a history of migraine

Abstract

Objective: To evaluate potential drug-drug interactions of ubrogepant and atogepant.Background: Ubrogepant and atogepant, calcitonin gene-related peptide (CGRP) receptor antagonists, are recently approved drugs for acute and preventive treatment of migraine, respectively. For patients with migraine who are prescribed atogepant for the preventive treatment of migraine, health care providers could prescribe ubrogepant for the acute treatment of breakthrough migraine attacks.Methods: A phase Ib, multi-center, open-label, fixed-sequence study was conducted in participants diagnosed with migraine for at least 1 year. To assess the primary objective of pharmacokinetic interactions in this phase I trial, the highest United States Food and Drug Administration-approved individual dose strengths of atogepant (60 mg once daily) and ubrogepant (100 mg) were utilized, with ubrogepant being administered on a fixed-dose schedule every 3 days, regardless of whether a participant was experiencing a migraine attack. Secondary endpoints included safety and tolerability. Clinical safety measurements were monitored throughout the study. Results:Of the 31 participants enrolled, 26 completed the study. A single dose of ubrogepant had no statistically significant effect on atogepant pharmacokinetics. Coadministration of ubrogepant with atogepant resulted in a 19% increase (geometric mean ratio 118.80, 90% confidence interval [CI] 108.69-129.84) in the ubrogepant area under the plasma concentration-time curve and a 26% increase (geometric mean ratio 125.63, 90% CI 105.58-149.48) in the ubrogepant maximum plasma concentration. These statistically significant changes in ubrogepant exposure were not clinically meaningful, and no new safety concerns were identified for the combination.

The pharmacotherapeutic management of episodic and chronic migraine with gepants

“…A single dose of ubrogepant had no statistically significant effect on atogepant pharmacokinetics. Co-administration of ubrogepant with atogepant resulted in no clinically meaningful changes in pharmacokinetic parameters [62].…”

Ubrogepant: Mechanism of action, clinical and translational science

“…Frequent use of non‐CGRP migraine medications can lead to medication overuse headache (MOH), and poor treatment of episodic migraine can lead to chronic migraine. However, CGRP receptor antagonists have shown no evidence that MOH occurs 17 . Progression of episodic migraine to a chronic state continues to be evaluated in the new era of CGRP‐targeted therapies; management of episodic migraine (i.e., reducing headache frequency) may prevent disease progression.…”

“…the optional second dose are recommended; patients with end-stage renal disease should avoid use. 16 Additionally, no clinically significant changes in ubrogepant pharmacokinetics have been identified when co-administered with oral contraceptives, acetaminophen, naproxen, esomeprazole, or other anti-migraine therapies (sumatriptan, erenumab, galcanezumab, or atogepant 17 ). 14 The capsaicin-induced dermal vasodilation (CIDV) model used for pharmacodynamic assessments (i.e., target engagement) of CGRP antagonist activity was first validated in the rhesus monkey then translated to humans.…”

“…In patients with severe hepatic or renal impairment, a dose reduction to 50 mg for the first and the optional second dose are recommended; patients with end‐stage renal disease should avoid use. 16 Additionally, no clinically significant changes in ubrogepant pharmacokinetics have been identified when co‐administered with oral contraceptives, acetaminophen, naproxen, esomeprazole, or other anti‐migraine therapies (sumatriptan, erenumab, galcanezumab, or atogepant 17 ). 14…”

The history and rationale of the development of new drugs for migraine treatment

“…Of the gepants, both atogepant and rimegepant were tested for migraine prevention. 101 102 103 Atogepant seems to be the most promising of this class of drugs, since it bears the best efficacy data 101 104 105 106 107 108 109 and was described as effective also for preventing chronic migraine. 110 Table 4 summarizes the clinical pharmacology of the available gepants.…”