Pharmacokinetics and Safety of Single and Multiple Daily Dosing of 75‐mg Rimegepant Orally Disintegrating Tablets in Healthy Chinese Adults: A Randomized Placebo‐Controlled Trial

Abstract

Rimegepant is an oral small‐molecule calcitonin gene‐related peptide antagonist for acute migraine treatment with or without aura and prevention of episodic migraine in adults. This was a rimegepant single‐ and multiple‐dose phase 1, randomized, placebo‐controlled, double‐blind study to evaluate the pharmacokinetics and confirm safety in healthy Chinese participants. Participants received a 75‐mg rimegepant orally disintegrating tablet (ODT) (N = 12) or matching placebo (N = 4) ODT on days 1 and 3–7 after fasting for pharmacokinetic assessments. Safety assessments included 12‐lead electrocardiograms, vital signs, clinical laboratory data, and adverse events (AEs). After a single dose (9 females, 7 males) median time to maximum plasma concentration was 1.5 hours; mean values were 937 ng/mL (maximum concentration), 4582 h*ng/mL (area under the concentration–time curve, 0 to infinity), 7.7 hours (terminal elimination half‐life), and 19.9 L/h (apparent clearance). Similar results were seen after 5 daily doses, with minimal accumulation. Six (37.5%) participants experienced ≥1 treatment‐emergent AE: 4 (33.3%) had received rimegepant and 2 (50.0%) had received placebo. All AEs were grade 1 and resolved by the end of the study with no deaths, serious/significant AEs, or AEs leading to discontinuation. Overall, single‐ and multiple‐dose rimegepant ODT 75 mg was safe and well‐tolerated in healthy Chinese adults with similar pharmacokinetics to non‐Asian healthy participants. Trial registration: This trial is registered with the China Center for Drug Evaluation (CDE): CTR20210569

The Pharmacokinetics, Safety, and Tolerability of Rimegepant 75 mg Are Similar in Elderly and Nonelderly Adults: A Phase 1, Open‐Label, Parallel‐Group, Single‐Dose Study

“…The key findings from this study included the following: rimegepant exposure (AUC) was approximately 5% higher in elderly participants than in nonelderly subjects, which was accompanied by a 5% decrease in C max for the elderly group; mean elimination (t 1/2el ) of rimegepant was somewhat longer in the elderly compared with nonelderly participants (15 vs 10 hours, respectively), although overall exposures were similar; and a single oral 75‐mg dose of rimegepant was safe and well tolerated in all participants, regardless of age. The overall results of this study for both elderly and nonelderly adults are generally consistent with prior pharmacokinetic data reported for rimegepant 21,23‐25,27,39 …”

“…The overall results of this study for both elderly and nonelderly adults are generally consistent with prior pharmacokinetic data reported for rimegepant. 21,[23][24][25]27,39 Limited pharmacokinetic data in the elderly are available for other gepants. A study with telcagepant reported no clinically meaningful pharmacokinetic differences when compared between young and elderly age groups.…”

“…20 Following oral administration, rimegepant pharmacokinetics are characterized by an absolute oral bioavailability of approximately 64% with peak plasma concentrations achieved after 1.5 hours. [21][22][23] In a multiple-ascending-oral-dose study, rimegepant showed a more-than-dose-proportional increase in exposure from 25 to 1500 mg following a single dose and from 75 to 600 mg following multiple doses. 24 Rimegepant is 96% protein bound and has limited metabolism (23%) with the formation of several minor inactive metabolites.…”

“…22 Approximately 77% of the dose is eliminated unchanged in feces and urine (two thirds of which are excreted in feces, which also includes unabsorbed drug based on the drug's bioavailability; and one third of which is excreted in urine) 25 with an average elimination half-life of 11 hours in healthy participants. 22,23 Rimegepant can be administered without dose modification to adults with mild to moderate hepatic impairment but is not recommended for use in those with severe hepatic impairment. 25 Rimegepant is primarily metabolized by cytochrome P450 (CYP) 3A4 and, to a lesser extent, by CYP2C9 in vitro.…”

No clinically relevant electrocardiogram effects in a randomized TQT study of single therapeutic/supratherapeutic rimegepant doses in healthy adults

“…The efficacy and safety of rimegepant have been demonstrated in several randomized, placebo-controlled clinical trials. [4][5][6][7][8] Rimegepant pharmacokinetics (PK) at the therapeutic dose of 75 mg have been published. 7,[9][10][11][12][13][14] The geometric mean maximum observed plasma concentration (C max ) is ~850 ng/mL after a single 75 mg dose with a time to C max (T max ) of ~1.5 h. 7 The area under the concentration-time curve (AUC) from 0 extrapolated to infinity is ~4500 ng•h/mL.…”