Zavegepant

Zavegepant is a calcitonin gene-related peptide (CGRP) receptor antagonist.

The relationship between pharmacodynamic activity and the mechanism by which zavegepant exerts its clinical effects is unknown.

No clinically relevant differences in resting blood pressure were observed when zavegepant 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.

Cardiac Electrophysiology

At a dose up to 4 times the recommended daily dose, zavegepant does not prolong the QT interval to any clinically relevant extent.

Absorption

Peak plasma concentration of zavegepant was observed at approximately 30 minutes after a single 10 mg dose of the nasal spray. After nasal spray administration of zavegepant, the absolute bioavailability is approximately 5%.

Zavegepant given as a single dose of the nasal spray displays slightly less than dose-proportional pharmacokinetics up to 40 mg (approximately 4 times the recommended dosage of 10 mg).

Following once daily dosing of zavegepant for 14 days there was no evidence of zavegepant accumulation.

Distribution

The mean apparent volume of distribution of intranasal zavegepant is approximately 1774 L. Plasma protein binding of zavegepant is approximately 90%.

Elimination

Metabolism

Zavegepant is primarily metabolized by CYP3A4 and to a lesser extent by CYP2D6, in vitro. After single IV dose of 5 mg [¹⁴C]-zavegepant, unchanged zavegepant was the most prevalent (approximately 90%) circulating component in the human plasma. No major metabolites (i.e., greater than 10%) of zavegepant were detected in plasma.

Excretion

The effective half-life of zavegepant following a 10 mg dose of the nasal spray is 6.55 hours. The mean apparent clearance of intranasal zavegepant is 266 L/h. Zavegepant is excreted mostly via the biliary/fecal route, while the renal route is a minor route of elimination. Following a single intravenous dose of 5 mg [¹⁴C]-zavegepant to healthy male subjects, approximately 80% and 11% of the dose was recovered as unchanged zavegepant in feces and urine, respectively.

Specific Populations

Patients with Hepatic Impairment

In a dedicated clinical study comparing the pharmacokinetics of zavegepant in subjects with moderate hepatic impairment (Child-Pugh B) to that of normal subjects (matched healthy controls), zavegepant C_max was 16% higher and AUC was 1.9-fold higher in patients with moderate hepatic impairment. These changes in exposures are not expected to be clinically significant, based on clinical safety experience and minimal accumulation of drug exposures. The impact of severe hepatic impairment (Child-Pugh C) on the pharmacokinetics of zavegepant was not studied.

Patients with Renal Impairment

The renal route plays a minor role in the clearance of zavegepant. No clinically significant effect on the pharmacokinetics of zavegepant is expected in subjects with estimated creatinine clearance (CLcr) 30 mL/min or greater. In patients with CLcr 15 to 29 mL/min, accumulation of uremic solutes can cause an increase in zavegepant exposures by inhibiting OATP transporters. Zavegepant has not been studied in patients with CLcr less than 15 mL/min.

Other Specific Populations

Age, sex, race, ethnicity, and body weight did not show clinically significant effects on the pharmacokinetics of zavegepant.

Drug Interaction Studies

In vitro Studies

Enzymes:

Zavegepant is a substrate of CYP3A4 and to a lesser extent CYP2D6. Zavegepant is not an inducer of CYP1A2, 2B6, or 3A4, or an inhibitor of CYP1A2, CYP2C9, 2C19, 2B6, 2D6, 2C8, and 3A4 at clinically relevant concentrations.

Transporters:

Zavegepant is a substrate for OATP1B3 and NTCP (see In vivo studies).

Zavegepant is also a substrate for the transporters P-gp, MATE1, and MATE2-K. Considering the minor contribution of the renal pathway in the clearance of zavegepant, coadministration of zavegepant with inhibitors of P-gp, MATE1, and MATE2-K inhibitors is not expected to result in a clinically significant effect on zavegepant pharmacokinetics.

Zavegepant is not a substrate for BCRP, OATP1B1, OAT1, OAT3, OCT2, BSEP, MRP2, MRP3, and MRP4.

Zavegepant is an inhibitor of OCT2, MATE1, and MATE2-K, but drug interactions for zavegepant are not expected at clinically relevant concentrations. Zavegepant is not an inhibitor of P-gp, BCRP, OAT1, OAT3, OATP1B1, and OATP1B3.

In vivo Studies

CYP3A4 Inhibitors:

Concomitant administration of a single dose of 10 mg zavegepant with itraconazole (a strong CYP3A4 and P-gp inhibitor), at steady state did not result in a clinically relevant effect on the exposures of zavegepant.

OATP1B3 or NTCP Inhibitors:

Concomitant administration of a single oral dose of 100 mg zavegepant with rifampin (an OATP1B3, NTCP inhibitor and a strong CYP3A inducer), at steady state resulted in increased zavegepant exposure (AUC by 2.3-fold and C_max by 2.2-fold). The observed change in zavegepant exposures is a composite effect of inhibition of OATP1B3 and NTCP transporters as well as induction of CYP3A enzymes. Concomitant administration of zavegepant with inhibitors of OATP1B3 or NTCP transporters may result in a significant increase in zavegepant exposure.

OATP1B3 or NTCP Inducers:

Concomitant administration of zavegepant with inducers of OATP1B3 or NTCP transporters has not been studied. However, since zavegepant is a substrate of OATP1B3 and NTCP, concomitant administration with inducers of these transporters may result in decreased zavegepant exposure.

Intranasal Decongestants:

The effect of concomitant intranasal decongestants on the pharmacokinetics of zavegepant nasal spray has not been evaluated. Concomitant administration of intranasal decongestants may decrease the systemic exposure of zavegepant and potentially the efficacy of zavegepant.

Other Drugs:

No significant pharmacokinetic interactions were observed when zavegepant was concomitantly administered with oral contraceptives (ethinyl estradiol) or sumatriptan.