Single Therapeutic and Supratherapeutic Doses of Ubrogepant Do Not Affect Cardiac Repolarization in Healthy Adults: Results From a Randomized Trial

Jakate, Abhijeet; Boinpally, Ramesh; Butler, Matthew J.; Lu, Kaifeng; McGeeney, Danielle; Periclou, Antonia

doi:10.1002/cpt.1696

Cited by 16 publications

(20 citation statements)

References 28 publications

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“…22,23 Furthermore, single ubrogepant doses of 400 mg were found to be safe and generally well tolerated in a thorough QT trial in healthy adults. 26 The observed decrease in acetaminophen C max when coadministered with ubrogepant and the minimal impact on AUC was not considered clinically relevant, as safety concerns with acetaminophen-associated toxicity are due to increased acetaminophen dose and exposure. 27 Coadministration of ubrogepant with naproxen did not alter the maximum plasma concentrations or overall exposures to either treatment.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of the pharmacokinetic interaction and safety of ubrogepant coadministered with acetaminophen or nonsteroidal anti-inflammatory drugs: A randomized trial

Jakate

Boinpally

Butler

et al. 2020

Cephalalgia Reports

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Background: Ubrogepant is a novel, oral calcitonin gene–related peptide receptor antagonist approved by the US Food and Drug Administration for acute treatment of migraine with or without aura in adults. Objectives: To assess potential pharmacokinetic (PK) drug–drug interactions in healthy participants and inform the safety and tolerability of ubrogepant alone and in combination with acetaminophen or nonsteroidal anti-inflammatory drugs (NSAIDs) in healthy participants and participants with migraine. Methods: Two phase 1, three-way crossover studies randomized healthy adults to 100 mg ubrogepant alone, 1000 mg acetaminophen or 500 mg naproxen alone, and 100 mg ubrogepant plus 1000 mg acetaminophen or 500 mg naproxen. Geometric mean ratios (GMRs) and 90% confidence intervals were calculated based on statistical comparison of maximum plasma drug concentration ( C max) and area under the plasma drug concentration–time curve (AUC) for treatment in combination versus alone. Two phase 3 randomized trials included adults with migraine. Treatment-emergent adverse events (TEAEs) were evaluated. Results: Time to C max and terminal elimination half-life for all treatments were unchanged when coadministered. Ubrogepant C max and AUC increased by approximately 40% when coadministered with acetaminophen. Acetaminophen C max decreased by 24% (GMR = 0.76) when coadministered with ubrogepant. There were no significant PK interactions between ubrogepant and naproxen. TEAE rates in the acetaminophen and NSAID rescue medication groups were similar to ubrogepant alone. Conclusions: Coadministration of ubrogepant and acetaminophen resulted in a statistically significant increase in ubrogepant exposure and a decrease in acetaminophen C max; however, these changes were not clinically relevant. No statistically or clinically relevant changes in PK were associated with ubrogepant and naproxen coadministration. No safety concerns were identified for ubrogepant alone or in combination with acetaminophen or NSAIDs.

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Section: Discussionmentioning

confidence: 99%

Evaluation of the pharmacokinetic interaction and safety of ubrogepant coadministered with acetaminophen or nonsteroidal anti-inflammatory drugs: A randomized trial

Jakate

Boinpally

Butler

et al. 2020

Cephalalgia Reports

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“…23,24 Ubrogepant is rapidly absorbed after oral administration, with a median time to maximum plasma drug concentration ( t max ) of 1.7 h and a terminal elimination half-life ( t ½ ) of 4.4 h for the 100-mg dose. 25 Ubrogepant has not been shown to induce or inhibit cytochrome P450 2D6 (CYP2D6), cytochrome P450 3A4 (CYP3A4), or p -glycoprotein at clinically relevant concentrations. Ubrogepant is metabolized primarily by CYP3A4, and the glucuronide conjugates (M15 and M20) of its oxidative metabolites (M9 and M8) are the primary circulating metabolites in human plasma.…”

Section: Introductionmentioning

confidence: 99%

The effect of multiple doses of ubrogepant on the pharmacokinetics of an oral contraceptive in healthy women: Results of an open-label, single-center, two-period, fixed-sequence study

Palcza

et al. 2020

Cephalalgia Reports

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Background: Ubrogepant is a novel, oral calcitonin gene–related peptide receptor antagonist for acute treatment of migraine. This study evaluated potential drug–drug interactions between ubrogepant and an oral contraceptive containing ethinyl estradiol (EE) and norgestimate (NGM). Methods: This open-label, single-center, two-period, fixed-sequence study enrolled healthy, postmenopausal or oophorectomized, adult women. In period 1, participants received a single oral dose of EE 0.035 mg/NGM 0.25 mg (EE-NGM) followed by a 7-day washout. In period 2, participants received oral ubrogepant 50 mg daily on days 1–14; single-dose EE-NGM was coadministered with ubrogepant on day 10. Pharmacokinetic parameters for plasma EE and norelgestromin (NGMN) were compared with and without ubrogepant. Results: Twenty-two participants aged 46–66 years were enrolled; 21 completed the study. Geometric mean ratios and 90% confidence intervals for the comparison of EE-NGM + ubrogepant to EE-NGM alone were contained within 0.80 and 1.25 for area under the plasma drug concentration–time curve (AUC) from time zero to infinity (AUC0–∞; 0.96 [0.91, 1.01]) and C max (0.91 [0.82, 1.004]) of NGMN and AUC0–∞ (0.97 [0.93, 1.01]) of EE, but not C max of EE (0.74 [0.69, 0.79]). Median t max of EE was delayed following EE-NGM + ubrogepant (3.0 h) versus EE-NGM alone (median of 1.5 h), whereas median t max of NGMN was unchanged (1.5 h). Geometric mean apparent terminal half-life ( t ½) was similar with and without ubrogepant for EE (23 vs. 21 h) and NGMN (36 h both conditions). All ubrogepant-related adverse events were mild or moderate. Conclusion: Ubrogepant did not demonstrate potential for clinically meaningful drug–drug interactions with an EE-NGM oral contraceptive. Trial registration: Not applicable (phase 1 trial)

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“…At doses twice the maximum recommended daily dose, ubrogepant does not prolong the QT interval to any clinically relevant extent [6], based on results of thorough QT study in healthy adults [9].…”

Section: Pharmacodynamicsmentioning

confidence: 99%

Ubrogepant: First Approval

Scott

2020

Drugs

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Ubrogepant (Ubrelvy™) is an orally administered, small molecule, highly-selective, calcitonin gene-related peptide (CGRP) antagonist that was developed by Allergan under license to Merck & Co. as an acute treatment for migraine. In December 2019, ubrogepant received its first global approval in the USA for the acute treatment of migraine (± aura) in adults. This article summarizes the milestones in the development of ubrogepant leading to its first global approval for the acute treatment of migraine (± aura) in adults. Ubrogepant (Ubrelvy™): Key points A calcitonin gene-related peptide receptor antagonist was being developed by Allergan under license to Merck & Co. for the acute treatment of migraine

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Single Therapeutic and Supratherapeutic Doses of Ubrogepant Do Not Affect Cardiac Repolarization in Healthy Adults: Results From a Randomized Trial

Cited by 16 publications

References 28 publications

Evaluation of the pharmacokinetic interaction and safety of ubrogepant coadministered with acetaminophen or nonsteroidal anti-inflammatory drugs: A randomized trial

Evaluation of the pharmacokinetic interaction and safety of ubrogepant coadministered with acetaminophen or nonsteroidal anti-inflammatory drugs: A randomized trial

The effect of multiple doses of ubrogepant on the pharmacokinetics of an oral contraceptive in healthy women: Results of an open-label, single-center, two-period, fixed-sequence study

Ubrogepant: First Approval

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