Abstract and Introduction
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. Co-administration 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.
Conclusion: The combination use of atogepant and ubrogepant was safe and well tolerated in adult participants with a history of migraine enrolled in the study. Pharmacokinetic changes during co-administration were not clinically meaningful.
Introduction
Newly approved and emerging pharmacologic migraine-specific treatment options are rapidly changing the treatment paradigm for individuals with migraine and healthcare providers. Episodic migraine (<15 headache days/month) accounts for the majority (92%) of people with migraine.[1] Migraine treatment involves acute and preventive treatment, and in some patients, both may be needed. Preventive treatment of episodic migraine improves function, quality of life, and societal burden;[2,3] however, >75% of people who are eligible for preventive treatment are not receiving treatment.[4,5] Moreover, patients with episodic migraine who experience inadequate acute treatment with over-the-counter medications, opioids, triptans, and barbiturates carry a higher risk of progression to chronic migraine (≥15 headache days/month).[6,7] For patients who seek care and receive an appropriate diagnosis, most discontinue or do not adhere to current standard-of-care preventive treatments due to suboptimal response rates and poor tolerability. For certain groups of people, these medications are contraindicated.[8–10] With new pharmacologic migraine treatment options emerging, management and alleviation of the burden of this disease is progressing as health care providers begin to integrate new migraine therapies into personalized treatment plans that comprehensively manage migraine attacks and move individuals closer to migraine freedom.[11,12]
The central role of calcitonin gene-related peptide (CGRP)[13] in migraine pathophysiology has led to the development of acute (e.g., oral gepants[14]) and preventive (e.g., oral gepants[14] and monoclonal antibodies[15]) treatments that target this mechanism. CGRP-targeted therapies have brought a new therapeutic option to patients with improved safety profiles that have not led to medication overuse headache[16,17] and extend treatment to patients with cardiovascular risk factors.[18–21] While CGRP-targeted therapies approved for preventive treatment of migraine have demonstrated significant reductions in mean headache days and improved patient function and quality of life both during and in between attacks,[22] patients may still experience breakthrough migraine attacks that require acute treatment; thus, clinical drug–drug interaction (DDI) studies on the concomitant use of established and recently approved (acute and preventive) migraine treatment options are needed to inform physicians on the pharmacokinetic (PK) interactions and safety of these anti-migraine therapy combinations.[23]
Here we focus on the combination of atogepant, an oral CGRP receptor antagonist approved for the preventive treatment of episodic migraine, and ubrogepant, an oral CGRP receptor antagonist approved for the acute treatment of migraine. Following oral administration in humans, atogepant and ubrogepant are rapidly absorbed with time to maximum plasma drug concentrations (Tmax) of ~1–2 h and ~ 1.5 h, respectively, and apparent terminal elimination half-life (t1/2) of ~11 and 5–7 h, respectively, resulting in minimal to no accumulation with repeated daily dosing of either agent.[24–26] Both atogepant and ubrogepant are extensively metabolized in the liver by cytochrome P450 3A4 (CYP3A4) and are substrates of several membrane transporters including P-glycoprotein (P-gp), organic-anion-transporting polypeptides (OATP) 1B1 and 1B3, and breast cancer resistance protein (BCRP).[25,26] In the phase III ADVANCE trial assessing atogepant for the preventive treatment of episodic migraine in adults with 4–14 migraine days/month, acute medication use days were reduced on average from 7 to 3 days/month.[21] Additionally, in the 12-week phase III PROGRESS trial evaluating atogepant for the preventive treatment of chronic migraine in adults with ≥15 migraine days/month, mean monthly acute medication use days were reduced by 6.2 and 6.7 days for participants receiving atogepant 60 mg once daily (QD) and 30 mg twice daily, respectively.[27] Although concomitant use of CGRP-targeting acute medications were prohibited in the trials, people with migraine who are taking atogepant for preventive treatment may additionally be prescribed ubrogepant for treatment of breakthrough attacks; thus, it is important to understand whether any DDIs exist between this combination.
Thus far, DDI studies of atogepant and ubrogepant with other migraine medications[28–31] and non-migraine medications[25,32–34] have demonstrated no clinically significant changes in safety or PK with concomitant use. Additionally, in a post hoc analysis, ubrogepant efficacy and safety were shown to be independent of a patients' prior history with triptans.[35] We hypothesized that the potential for a clinically significant interaction when ubrogepant and atogepant are co-administered is low;[25,26] however, the overlapping effects of two co-administered oral gepants, both of which are substrates of CYP3A4 and P-gp, is unknown. Thus, we report here, the results from a phase I DDI study of atogepant and ubrogepant to evaluate the potential for a PK interaction and provide safety and tolerability information when the two are co-administered in participants with migraine.
Headache. 2023;63(3):322-332. © 2023 Blackwell Publishing