Chemical formula: C₂₈H₂₈F₂N₆O₃ Molecular mass: 534.568 g/mol PubChem compound: 51049968
Rimegepant selectively binds with high affinity to the human calcitonin gene-related peptide (CGRP) receptor and antagonizes CGRP receptor function.
The relationship between pharmacodynamic activity and the mechanism(s) by which rimegepant exerts its clinical effects is unknown.
Following oral administration, rimegepant is absorbed with the maximum concentration at 1.5 hours. Following a supratherapeutic dose of 300 mg, the absolute oral bioavailability of rimegepant was approximately 64%.
Following administration of rimegepant under fed conditions with a high-fat or low-fat meal, Tmax was delayed by 1 to 1.5 hours. A high-fat meal reduced Cmax by 42 to 53% and AUC by 32 to 38%. A lowfat meal reduced Cmax by 36% and AUC by 28%. Rimegepant was administered without regard to food in clinical safety and efficacy studies.
The steady state volume of distribution of rimegepant is 120 l. Plasma protein binding of rimegepant is approximately 96%.
Rimegepant is primarily metabolized by CYP3A4 and to a lesser extent by CYP2C9. Rimegepant is primarily eliminated in unchanged form (~77% of the dose) with no major metabolites (i.e., >10%) detected in plasma.
Based on in vitro studies, rimegepant is not an inhibitor of CYP1A2, 2B6, 2C9, 2C19, 2D6, or UGT1A1 at clinically relevant concentrations. However, rimegepant is a weak inhibitor of CYP3A4 with time-dependent inhibition. Rimegepant is not an inducer of CYP1A2, CYP2B6, or CYP3A4 at clinically relevant concentrations.
The elimination half-life of rimegepant is approximately 11 hours in healthy subjects. Following oral administration of [14C]-rimegepant to healthy male subjects, 78% of the total radioactivity was recovered in feces and 24% in urine. Unchanged rimegepant is the major single component in excreted feces (42%) and urine (51%).
In vitro, rimegepant is a substrate of P-gp and BCRP efflux transporters. Inhibitors of P-gp and BCRP efflux transporters may increase plasma concentrations of rimegepant.
Rimegepant is not a substrate of OATP1B1 or OATP1B3. Considering its low renal clearance, rimegepant was not evaluated as a substrate of the OAT1, OAT3, OCT2, MATE1, or MATE2-K.
Rimegepant is not an inhibitor of P-gp, BCRP, OAT1, or MATE2-K at clinically relevant concentrations. It is a weak inhibitor of OATP1B1 and OAT3.
Rimegepant is an inhibitor of OATP1B3, OCT2, and MATE1. Concomitant administration of rimegepant with metformin, a MATE1 transporter substrate, resulted in no clinically significant impact on either metformin pharmacokinetics or on glucose utilization. No clinical drug interactions are expected for rimegepant with OATP1B3 or OCT2, at clinically relevant concentrations.
Rimegepant exhibits greater than dose proportional increases in exposure following single oral administration, which appears to be related to a dose-dependant increase in bioavailability.
No clinically significant differences in the pharmacokinetics of rimegepant were observed based on age, sex, race/ethnicity, body weight, migraine status, or CYP2C9 genotype.
In a dedicated clinical study comparing the pharmacokinetics of rimegepant in subjects with mild (estimated creatinine clearance [CLcr] 60-89 ml/min), moderate (CLcr 30-59 ml/min), and severe (CLcr 15-29 ml/min) renal impairment to that with normal subjects (healthy pooled control), a less than 50% increase in total rimegepant exposure was observed following a single 75 mg dose. The unbound AUC of rimegepant was 2.57-fold higher in subjects with severe renal impairment. Rimegepant has not been studied in patients with end-stage renal disease (CLcr <15 ml/min).
In a dedicated clinical study comparing the pharmacokinetics of rimegepant in subjects with mild, moderate, and severe hepatic impairment to that with normal subjects (healthy matched control), the exposure of rimegepant (unbound AUC) following a single 75 mg dose was 3.89-fold higher in subjects with severe impairment (Child-Pugh class C). There were no clinically meaningful differences in the exposure of rimegepant in subjects with mild (Child-Pugh class A) and moderate hepatic impairment (Child-Pugh class B) compared to subjects with normal hepatic function.
Non-clinical data reveal no special hazard for rimegepant in humans based on conventional studies of safety pharmacology, repeat-dose toxicity, genotoxicity, phototoxicity, reproduction or development, or carcinogenic potential.
Rimegepant-related effects at higher doses in repeat-dose studies included hepatic lipidosis in mice and rats, intravascular hemolysis in rats and monkeys, and emesis in monkeys. These findings were observed only at exposures considered sufficiently in excess of the maximum human exposure indicating little relevance to clinical use (≥12 times [mice] and ≥ 49 times [rats] for hepatic lipidosis, ≥95 times [rats] and ≥9 times [monkeys] for intravascular hemolysis, and ≥37 times for emesis [monkeys]).
In a fertility study in rats, rimegepant-related effects were noted only at the high dose of 150 mg/kg/day (decreased fertility and increased pre-implantation loss) that produced maternal toxicity and systemic exposures ≥95 times the maximum human exposure. Oral administration of rimegepant during organogenesis resulted in foetal effects in rats but not rabbits. In rats, decreased foetal body weight and increased incidence of foetal variations were observed only at the highest dose of 300 mg/kg/day that produced maternal toxicity at exposures approximately 200 times the maximum human exposure. Additionally, rimegepant had no effects on pre- and postnatal development in rats at doses up to 60 mg/kg/day (≥24 times the maximum human exposure) or on growth, development, or reproductive performance of juvenile rats at doses up to 45 mg/kg/day (≥14 times the maximum human exposure).
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