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Abstract Details

Phase 1 and 2 Safety, Tolerability and Pharmacokinetics of Single and Multiple Dose Rimegepant as Compared to the Predicted Clinically Efficacious Dose Range
Headache
P13 - Poster Session 13 (5:30 PM-6:30 PM)
7-004
Evaluate the safety, tolerability and pharmacokinetics (PK) of rimegepant in healthy subjects, including identification of a maximum tolerated dose (MTD), relative to the predicted clinically therapeutic dose range.
The transition from pharmaceutical discovery to clinical development is often challenging, particularly identifying the target safe and efficacious human dose.
Allometric scaling from discovery assays predicted the therapeutic dose range of rimegepant for acute treatment of migraine to be 70 to 140 mg. The dose range was projected by considering efficacy in the marmoset facial blood flow assay, volume of distribution, plasma clearance and oral bioavailability. On that basis, a Phase 1 study was designed to evaluate the safety, tolerability and PK of single (SAD) or multiple (MAD) dose rimegepant. For SAD, 8 healthy subjects received a single dose (25, 75, 150, 300, 600, 900 or 1,500 mg) of rimegepant or placebo. For MAD, 8 healthy subjects received daily doses (75, 150, 300, 450 or 600 mg) of rimegepant or placebo.
Single doses of rimegepant were well tolerated up to 1,500 mg and likewise multiple doses up to 600 mg for 14 days without serious adverse events (AEs). A maximum tolerated dose was not reached despite achieving exposures that were >50× higher (Cmax 20,499 ng/mL and AUC 198,750 ng•h/mL) than those observed near the low predicted therapeutic dose 75 mg (Cmax 784 ng/mL and AUC 3,729 ng•h/mL).
Rimegepant appeared to be safe and well tolerated over the doses tested in this healthy population, including exposures >50× beyond the lowest predicted efficacious dose. Discovery assay predictions of 70 to 140 mg were confirmed in Phase 2b which identified 75 mg as fully efficacious in 2-hour endpoints of pain, nausea, photophobia, and phonophobia; and where a single dose produced a lasting effect through 48 hours postdose.