NURTEC ODT 10 Clinical Pharmacology

rimegepant

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10.1 Mechanism of Action

Rimegepant is a calcitonin gene-related peptide receptor antagonist. 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.

10.2 Pharmacodynamics

No clinically relevant differences in resting blood pressure were observed when rimegepant was concomitantly administered with sumatriptan (12 mg subcutaneous, given as two 6 mg doses separated by one hour) compared with sumatriptan alone to healthy volunteers.

Abuse liability has not been studied in humans or in animals.   

Cardiac Electrophysiology

In a double-blind, randomized, placebo- and positive-controlled, crossover ECG assessment study in healthy subjects (N=38), single 75 mg and 300 mg doses of rimegepant did not show any pharmacodynamic effect on the QTc interval.

10.3 Pharmacokinetics

CYP2C9 polymorphism

Rimegepant Cmax and AUC0-inf were similar in CYP2C9 intermediate metabolizers (i.e., *1/*2, *2/*2, *1/*3, n=43) as compared to normal metabolizers (i.e., *1/*1, n=72). Adequate PK data are not available from CYP2C9 poor metabolizers (i.e., *2/*3, n=2). Since the contribution of CYP2C9 to rimegepant metabolism is considered minor, CYP2C9 polymorphism is not expected to significantly affect its exposure.

Absorption

Following oral administration of NURTEC ODT, rimegepant is absorbed with the maximum concentration at 1.5 to 2.0 hours. The absolute oral bioavailability of rimegepant is approximately 64%.

Distribution:

The steady state volume of distribution of rimegepant is 120 L. Plasma protein binding of rimegepant is approximately 96%.

Metabolism:

Rimegepant is primarily metabolized by CYP3A4 and to a lesser extent by CYP2C9. Rimegepant is the primary form (~77% ) with no major metabolites (i.e., > 10%) detected in plasma.

Elimination:

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%). 

Special Populations and Conditions

  • Geriatrics: In pharmacokinetic studies, no clinically significant pharmacokinetic differences were observed between elderly (≥ 65 years) and younger (18-45 years) subjects.
  • Sex: No clinically significant differences in the pharmacokinetics of rimegepant were observed based on sex.
  • Genetic Polymorphism: No clinically significant differences in the pharmacokinetics of rimegepant were observed based on CYP2C9 genotype.
  • Ethnic Origin: No clinically significant differences were observed in studies where the pharmacokinetics of rimegepant in White, Black, and Japanese study participants were assessed.
  • Hepatic Insufficiency: 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 (Cmax and AUC) following single 75 mg dose was approximately 2-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 (see 4.2 Recommended Dose and Dosage Adjustment, Hepatic impairment).
  • Renal Insufficiency: 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 matched control), total rimegepant exposure was increased by 6%, 40%, and 4%, respectively following a single 75 mg dose. NURTEC ODT has not been studied in patients with end-stage renal disease (CLcr < 15 mL/min) and in patients undergoing dialysis (see 4.2 Recommended Dose and Dosage Adjustment, Renal impairment).
  • Obesity: No clinically significant differences in the pharmacokinetics of rimegepant were observed based on body weight.
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10 Clinical Pharmacology

10.1 Mechanism of Action

Rimegepant is a calcitonin gene-related peptide receptor antagonist. 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.

10.2 Pharmacodynamics

No clinically relevant differences in resting blood pressure were observed when rimegepant was concomitantly administered with sumatriptan (12 mg subcutaneous, given as two 6 mg doses separated by one hour) compared with sumatriptan alone to healthy volunteers.

Abuse liability has not been studied in humans or in animals.   

Cardiac Electrophysiology

In a double-blind, randomized, placebo- and positive-controlled, crossover ECG assessment study in healthy subjects (N=38), single 75 mg and 300 mg doses of rimegepant did not show any pharmacodynamic effect on the QTc interval.

10.3 Pharmacokinetics

CYP2C9 polymorphism

Rimegepant Cmax and AUC0-inf were similar in CYP2C9 intermediate metabolizers (i.e., *1/*2, *2/*2, *1/*3, n=43) as compared to normal metabolizers (i.e., *1/*1, n=72). Adequate PK data are not available from CYP2C9 poor metabolizers (i.e., *2/*3, n=2). Since the contribution of CYP2C9 to rimegepant metabolism is considered minor, CYP2C9 polymorphism is not expected to significantly affect its exposure.

Absorption

Following oral administration of NURTEC ODT, rimegepant is absorbed with the maximum concentration at 1.5 to 2.0 hours. The absolute oral bioavailability of rimegepant is approximately 64%.

Distribution:

The steady state volume of distribution of rimegepant is 120 L. Plasma protein binding of rimegepant is approximately 96%.

Metabolism:

Rimegepant is primarily metabolized by CYP3A4 and to a lesser extent by CYP2C9. Rimegepant is the primary form (~77% ) with no major metabolites (i.e., > 10%) detected in plasma.

Elimination:

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%). 

Special Populations and Conditions

  • Geriatrics: In pharmacokinetic studies, no clinically significant pharmacokinetic differences were observed between elderly (≥ 65 years) and younger (18-45 years) subjects.
  • Sex: No clinically significant differences in the pharmacokinetics of rimegepant were observed based on sex.
  • Genetic Polymorphism: No clinically significant differences in the pharmacokinetics of rimegepant were observed based on CYP2C9 genotype.
  • Ethnic Origin: No clinically significant differences were observed in studies where the pharmacokinetics of rimegepant in White, Black, and Japanese study participants were assessed.
  • Hepatic Insufficiency: 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 (Cmax and AUC) following single 75 mg dose was approximately 2-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 (see 4.2 Recommended Dose and Dosage Adjustment, Hepatic impairment).
  • Renal Insufficiency: 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 matched control), total rimegepant exposure was increased by 6%, 40%, and 4%, respectively following a single 75 mg dose. NURTEC ODT has not been studied in patients with end-stage renal disease (CLcr < 15 mL/min) and in patients undergoing dialysis (see 4.2 Recommended Dose and Dosage Adjustment, Renal impairment).
  • Obesity: No clinically significant differences in the pharmacokinetics of rimegepant were observed based on body weight.

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