Ensifentrine

Ensifentrine is a small molecule that is an inhibitor of the PDE3 and PDE4 enzymes. PDE3 primarily hydrolyzes the second-messenger molecule cyclic adenosine monophosphate (cAMP) but is also capable of hydrolyzing cyclic guanosine monophosphate (cGMP). PDE4 hydrolyzes cAMP only. Inhibition of PDE3 and PDE4 results in accumulation of intracellular levels of cAMP and/or cGMP, resulting in various downstream signalling effects.

Cardiac Electrophysiology

QTc interval prolongation was studied in a randomized, double-blind, placebo- and positivecontrolled, 4-period crossover study in 32 healthy subjects. At 3 times the maximum recommended dose, clinically significant QTc interval prolongation was not observed.

Exposure to ensifentrine increased approximately 1.4-fold greater than dose proportional following a dose 3 times the recommended dosage. Steady-state was attained by Day 3 following twice-daily dosing. Population pharmacokinetic analysis predicts accumulation of ensifentrine of 1.3 and 1.4-fold for C_max and AUC in healthy subjects and 1.4 and 1.5-fold for C_max and AUC in subjects with COPD. Population pharmacokinetic analysis indicates that relative bioavailability in subjects with COPD is approximately 35% lower when compared to healthy subjects. Exposure to ensifentrine was associated with high inter-subject variability.

Absorption

Following inhaled administration of ensifentrine in healthy subjects and subjects with COPD, ensifentrine C_max was attained around 0.6 to 1.5 hours after dosing.

A randomized, 2-period, cross-over study assessing systemic exposure following inhalation of 2 times the recommended dose of ensifentrine with and without charcoal block demonstrated that the majority of an inhaled dose (approximately 90%) is delivered to the lung from which it is absorbed.

Distribution

Apparent central and peripheral volume of distribution for ensifentrine in healthy subjects were 2700 L and 1820 L, respectively, as estimated in population PK analysis. In patients with COPD, apparent central and peripheral volumes were estimated as 8150 L and 5490 L, respectively.

In vitro plasma protein binding of ensifentrine is approximately 90%.

Elimination

Following twice-daily administration for 6 days, terminal elimination half-life ranged from 10.6 to 12.6 hours in healthy subjects and subjects with COPD (1.5 mg to 12 mg twice daily).

Metabolism

Following administration of a single nebulized dose, 8 times the recommended dose of ensifentrine, unchanged ensifentrine was identified as the major drug-related component in human plasma, accounting for 96 and 99% of the drug-related material identified in Tmax and time-normalized (0-24 h) plasma samples, respectively.

The primary metabolic routes for ensifentrine are oxidative (hydroxylation, O-demethylation) followed by conjugation (e.g., glucuronidation).

In vitro results indicate that, at physiologically relevant concentrations, ensifentrine was predominantly metabolized by CYP2C9 and to a lesser extent by CYP2D6.

Excretion

The majority of ensifentrine is excreted in feces. After a 3 mg nebulized dose, urinary elimination of unchanged ensifentrine was negligible (<0.3% of the dose).

Specific Populations

Population pharmacokinetic analysis showed no evidence of a clinically significant effect of demographic covariates such as age (18 to 80 years), sex (56% male), ethnicity (Hispanic, NonHispanic), race (white, black) and weight (42 to 180 kg) on ensifentrine pharmacokinetics.

Patients with Renal Impairment

A dedicated study with ensifentrine evaluating the effect of renal impairment on the pharmacokinetics of ensifentrine was not conducted.

The effect of renal impairment on the exposure to ensifentrine for up to 24 weeks was evaluated in a population pharmacokinetic analysis. Estimated glomerular filtration rate (eGFR) varied from 25.5 to 191 mL/min representing a range of moderate to no renal impairment. While continuous covariates of renal function did not show a significant correlation with ensifentrine exposure, categorical characterization of renal function indicated a 25% mean reduction in the apparent clearance in subjects with moderate renal impairment. The pharmacokinetics of ensifentrine in severe renal impairment (creatine clearance <30 mL/min) or subjects with end-stage renal disease have not been evaluated.

Patients with Hepatic Impairment

The pharmacokinetics of ensifentrine were evaluated in subjects with moderate (Child-Pugh Class B) (N=10) to severe (Child-Pugh Class C) (N=2) hepatic impairment. Ensifentrine C_max and AUCinf were approximately 2.3-fold and 2.2-fold higher in subjects with moderate hepatic impairment compared with healthy controls. Ensifentrine C_max and AUCinf were approximately 1.2-fold and 2.3-fold higher in subjects with severe hepatic impairment compared with healthy controls (N=7). Population PK analysis did not identify markers of liver function (ALT, AST, bilirubin, and ALP) as a significant covariate for exposure of ensifentrine.

Drug Interaction Studies

Effect of Other Drugs on Ensifentrine

Clinical Studies:

Ensifentrine and Cytochrome P450: Ensifentrine C_max and AUC0-inf were 1.4-fold and 1.6-fold higher; respectively, when a 3 mg single dose of ensifentrine was concomitantly administered with CYP2C9 inhibitor fluconazole (200 mg twice daily).

In Vitro Studies:

Ensifentrine and Efflux Transporters: Ensifentrine is not a substrate of the efflux transporter P-glycoprotein (P-gp). Ensifentrine is a substrate of breast cancer resistance protein (BCRP).

Ensifentrine and Uptake Transporters: Ensifentrine is not a substrate of the uptake transporters OATP1B1 or OATP1B3.

Effect of Ensifentrine on Other Drugs

In Vitro Studies:

Ensifentrine and Cytochrome P450: At therapeutically relevant concentrations, ensifentrine does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A4.

Ensifentrine and Efflux Transporters: At therapeutically relevant concentrations, ensifentrine is not an inhibitor of either BCRP or P-gp.

Ensifentrine and Uptake Transporters: Ensifentrine does not inhibit the transporters, OATP1B1, OATP1B3, OAT1, OAT3, OCT2, MATE1 or MATE2-K, at therapeutically relevant concentrations.