Abstract
OBJECTIVE: The objective of this study was to investigate the pharmacokinetics of rimegepant in participants with mild, moderate, or severe renal impairment compared to healthy adults with normal renal function. BACKGROUND: Rimegepant is a calcitonin gene-related peptide receptor antagonist approved in the United States for treatment of acute and preventive treatment of migraine. METHODS: In this Phase 1, open-label, four-group, pharmacokinetic study, 36 participants were grouped by degree of renal impairment according to estimated glomerular filtration rate (eGFR): normal; mild (60-89 mL/min/1.73 m(2)); moderate (30-59 mL/min/1.73 m(2)); and severe (<30 mL/min/1.73 m(2)). Participants received a single 75-mg oral rimegepant tablet to determine total and unbound plasma rimegepant concentrations using both matched and pooled control analysis. The study enrollment period began on October 17, 2017, and concluded on March 27, 2018. RESULTS: For mild, moderate, and severe renal impairment groups, respectively, compared with matched control groups, total geometric least-square mean ratios (90% confidence intervals) were 1.06 (0.75-1.52), 1.40 (0.97-2.02), and 1.04 (0.70-1.57) for area under the concentration-time curve from time zero to infinity (AUC(0-inf)) and 1.20 (0.75-1.92), 0.76 (0.42-1.37), and 0.90 (0.50-1.62) for maximum observed concentration (C(max)). Geometric mean ratios of unbound AUC(0-inf) were 1.22 (0.82-1.82), 1.84 (1.30-2.61), and 2.57 (1.86-3.56) in the mild, moderate, and severe renal impairment groups, respectively, using the pooled control group analysis. Relationships for eGFR versus total plasma concentrations and pharmacokinetic parameters showed no significant trends; however, there was a statistically significant (p < 0.05) relationship showing greater unbound rimegepant AUC(0-inf) and C(max) in participants with lower eGFR. CONCLUSIONS: Among participants with mild, moderate, or severe renal impairment, a ≤40% increase in total rimegepant exposure was observed following single-dose 75-mg administration. Unbound rimegepant AUC(0-inf) exposure increased 1.8- and 2.6-fold in participants with moderate and severe renal impairment, respectively. The pharmacokinetic results from this study and safety data from other clinical studies were used to support rimegepant dosing recommendations in patients with renal impairment. Rimegepant has not been studied in patients with end-stage renal disease or in patients on dialysis and should be avoided in those populations.