Etripamil

Etripamil is an L-type calcium influx inhibitor (slow channel blocker or calcium ion antagonist). Etripamil exerts its pharmacologic effect by modulating the influx of ionic calcium across the cell membrane of the AV nodal cells as well as arterial smooth muscles and contractile myocardial cells. By interrupting reentry at the AV node, etripamil can restore sinus rhythm in patients with PSVT.

Cardiac Electrophysiology

Etripamil prolonged the baseline PR interval by 8% to 10% approximately 5 minutes following an intranasal dose of 70 mg. This PR interval prolongation begins to decline shortly after the etripamil maximum concentration (C_max) and falls below the 8 to 10% threshold between 25 and 50 minutes. Etripamil mean maximum change from baseline PR interval was approximately 13% following a single 70 mg dose and 20% following two 70 mg doses in the NODE-103 trial. At a dose of 1 to 2 times the maximum recommended therapeutic dose, etripamil does not prolong the QTc interval.

Hemodynamics

In patients with induced supraventricular tachycardia in an electrophysiology laboratory, a single intranasal etripamil administration was associated with a maximal systolic blood pressure reduction of approximately 21 mm Hg with 140 mg, 17 mm Hg with 105 mg (1.5 x maximum approved dose), and 3 mm Hg with 70 mg dose. No reduction in blood pressure was observed with etripamil 35 mg dose

After one 70 mg dose of etripamil, mean (%CV) area under the concentration-time curve (AUC) is approximately 5461 (51.6%) ng*min/mL and the C_max is approximately 99 (64.6%) ng/mL. After a second 70 mg dose of etripamil administered 10 minutes after the first dose, mean (%CV) AUC is approximately 7721 (50.3%) ng*min/mL and the C_max is approximately 132 (59.1%) ng/mL.

Absorption

Etripamil median (range) time to C_max (T_max) is 7 minutes (3 to 20 minutes) following a single intranasal administration of 70 mg. Median T_max is 13 minutes (3 to 35 minutes) following a second intranasal administration of 70 mg. Distribution Etripamil mean apparent volume of distribution ranges from approximately 2200 to 3500 L. Etripamil plasma protein binding is approximately 50%.

Elimination

Average etripamil concentration fell by approximately 60% of its peak value (C_max) at 25 minutes and 80% of the C_max by 60 minutes after dosing. Subsequently, concentrations decrease at a slower rate, and this decline is associated with a half-life of approximately 2.5 hours.

Metabolism

Etripamil metabolic pathways include hydrolysis, demethylation, N-dealkylation, and secondary oxidation, glucuronidation, and taurine conjugation. Etripamil is primarily metabolized by blood esterases and hepatic metabolism, primarily via CYP3A4, and CYP3A5. Etripamil contains a methyl ester which renders it metabolically sensitive to bloodborne esterases.

Excretion

After a single dose of radiolabeled intranasal etripamil 70 mg to healthy subjects, approximately 29% of the dose was recovered in urine (<0.05% unchanged), 26% was recovered in feces (<0.05% unchanged), and the remainder was recovered on nose and face tissues. Approximately 71% of the total administered dose was recovered in 7-10 days.

Specific Populations

No clinically significant differences in the pharmacokinetics of etripamil were observed based on age (19 to 56 years old), body weight (49 to 91 kg), height (157 to 194 cm), sex, or race (Caucasian, Asian, or African American). The effect of renal impairment (eGFR <90 mL/min) or hepatic impairment (Child Pugh A, B, or C) on etripamil pharmacokinetics is unknown. It is unknown whether etripamil is dialyzable.

Drug Interaction Studies

Clinical Studies and Model-Informed Approaches

Negative chronotropic and inotropic agents: Etripamil was safely administered to patients taking beta blockers or calcium channel blockers. In RAPID, 107 (42%) patients were on beta blockers and 81 (32%) patients were on calcium channel blockers.

In Vitro Studies

Cytochrome P450 (CYP) Enzymes: Etripamil is a CYP3A4 and CYP3A5 substrate. Etripamil inhibits CYP2D6, CYP3A4, and CYP2C9 but does not inhibit CYP2B6 or CYP2C8. Etripamil does not induce CYP1A2, CYP2B6, or CYP3A4.

Transporter Systems: Etripamil is a substrate of P-gp and OATP1B1, but not BCRP, OATP1B3, OCT1, OCT2, OAT1, OAT3, MATE1, and MATE2-K. Etripamil inhibits P-gp and MATE1, but not BCRP, BSEP, MATE2-K, OAT1, OAT3, OATP1B1, OATP1B3, OCT1, and OCT2.