Revefenacin

Revefenacin is a long-acting muscarinic antagonist, which is often referred to as an anticholinergic. It has similar affinity to the subtypes of muscarinic receptors M1 to M5. In the airways, it exhibits pharmacological effects through inhibition of M3 receptor at the smooth muscle leading to bronchodilation. The competitive and reversible nature of antagonism was shown with human and animal origin receptors and isolated organ preparations. In preclinical in vitro as well as in vivo models, prevention of methacholine- and acetylcholine-induced bronchoconstrictive effects was dose-dependent and lasted longer than 24 hours. The clinical relevance of these findings is unknown. The bronchodilation following inhalation of revefenacin is predominantly a site-specific effect.

Cardiac Electrophysiology

QTc interval prolongation was studied in a randomized, double-blind, placebo- and positive‑controlled, single dose, crossover trial in 48 healthy subjects. Following a single dose of revefenacin 700 mcg (4 times the recommended dosage), no effects on prolongation of QTc interval were observed.

Revefenacin pharmacokinetic parameters are presented as the mean [standard deviation (SD)] unless otherwise specified. Following repeat dosing of inhaled revefenacin, steady-state was achieved within 7 days with <1.6‑fold accumulation. Revefenacin exposure (C_max and AUC) in COPD patients is approximately 60% lower as compared to healthy subjects. Exposure (C_max and AUC) of the active metabolite in COPD patients is approximately 2-fold higher as compared to healthy subjects. Revefenacin C_max was 0.16 ng/mL (0.11) and AUC was 0.22 ng·hr/mL (0.20) at steady-state after inhaled revefenacin 175 mcg dose in COPD patients. C_max of the active metabolite was 0.20 ng/mL (0.13) and AUC was 0.69 ng·hr/mL (0.53) at steady-state after inhaled revefenacin 175 mcg dose in COPD patients.

Revefenacin and its active metabolite exposure increased in a slightly greater than dose proportional manner with increasing revefenacin dose. After single or multiple once-daily dosing of revefenacin, both AUC and C_max of revefenacin and its active metabolite increased by approximately 11-fold over the 88 to 700 mcg (8‑fold) dose range.

Absorption

Following inhaled administration of revefenacin in healthy subjects or COPD patients, C_max of revefenacin and its active metabolite occurred at the first postdose sampling time which ranged from 14 to 41 minutes after start of nebulization. The absolute bioavailability following an oral dose of revefenacin is low (<3%).

Distribution

Following intravenous administration to healthy subjects, the mean steady-state volume of distribution of revefenacin was 218 L suggesting extensive distribution to tissues. In vitro protein binding of revefenacin and its active metabolite in human plasma was on average 71% and 42%, respectively.

Elimination

The terminal half-life of revefenacin and its active metabolite after once-daily dosing of revefenacin in COPD patients is 22 to 70 hours.

Metabolism

In vitro and in vivo data showed that revefenacin is primarily metabolized via hydrolysis of the primary amide to a carboxylic acid forming its major active metabolite. Following inhaled administration of revefenacin in COPD patients, conversion to its active metabolite occurred rapidly, and plasma exposures of the active metabolite exceeded those of revefenacin by approximately 4- to 6-fold (based on AUC). The active metabolite is formed by hepatic metabolism and possesses activity at target muscarinic receptors that is lower (approximately one-third to one-tenth) than that of revefenacin. It could potentially contribute to systemic antimuscarinic effects at therapeutic doses.

Excretion

Following administration of a single intravenous dose of radiolabeled revefenacin to healthy male subjects, approximately 54% of total radioactivity was recovered in the feces and 27% was excreted in the urine. Approximately 19% of the administered radioactive dose was recovered in the feces as the active metabolite. Following administration of a single radiolabeled oral dose of revefenacin, 88% of total radioactivity was recovered in the feces and <5% was present in urine, suggesting low oral absorption. There was minimal renal excretion (<1%) of revefenacin and its active metabolite following inhaled administration of revefenacin in COPD patients.

Specific Populations

Population pharmacokinetic analysis showed no evidence of a clinically significant effect of age (44 to 79 years), gender (59% male), smoking status (42% current smoker), or weight (46 to 155 kg) on systemic exposure of revefenacin and its active metabolite.

Patients with Hepatic Impairment

The pharmacokinetics of revefenacin was evaluated in subjects with moderate hepatic impairment (Child-Pugh score of 7-9). There was no increase in C_max of revefenacin and 1.5-fold increase in C_max of the active metabolite. There was 1.2-fold increase in AUC of revefenacin and up to 4.7-fold increase in AUC of the active metabolite. Revefenacin has not been evaluated in subjects with severe hepatic impairment.

Patients with Renal Impairment

The pharmacokinetics of revefenacin was evaluated in subjects with severe renal impairment (CrCl <30 mL/min). There was 1.5-fold increase in C_max of revefenacin and up to 2-fold increase in C_max of the active metabolite. There was up to 2.3‑fold increase in AUC_inf of revefenacin; the active metabolite exposure (AUC_inf) was increased by up to 2.5-fold. Revefenacin has not been evaluated in subjects with end-stage renal disease.

Drug Interactions

Revefenacin and Cytochrome P450

Neither revefenacin nor its active metabolite inhibits the following cytochrome P450 isoforms: CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4/5. Neither revefenacin nor its active metabolite induces CYP1A2, CYP2B6, and CYP3A4/5.

Revefenacin and Efflux Transporters

Revefenacin is a substrate of P-gp and BCRP. Neither revefenacin nor its active metabolite is an inhibitor of these efflux transporters.

Revefenacin and Uptake Transporters

The active metabolite of revefenacin is a substrate of OATP1B1 and OATP1B3. Neither revefenacin nor its active metabolite is an inhibitor of the uptake transporters OATP1B1, OATP1B3, OAT1, OAT3, or OCT2.