Vibegron

Vibegron is a selective human beta-3 adrenergic receptor agonist. Activation of the beta-3 adrenergic receptor increases bladder capacity by relaxing the detrusor smooth muscle during bladder filling.

Vibegron’s exposure-response relationship and the time course of pharmacodynamic response are not fully characterized.

Blood Pressure

In a 4-week, randomized, placebo-controlled, ambulatory blood pressure study in OAB patients (n=200), daily treatment with vibegron 75 mg was not associated with clinically significant changes in blood pressure. Subjects enrolled in this study had a mean age of 59 years and 75% were female. Thirty-five percent of subjects had pre-existing hypertension at baseline and 29% of all subjects were taking at least 1 concomitant antihypertensive medication.

Cardiac Electrophysiology

Vibegron does not prolong the QT interval to any clinically relevant extent at a single dose 5.3 times the approved recommended dose.

Mean vibegron C_max and AUC increased in a greater than dose-proportional manner up to 600 mg (8 times the approved recommended dosage). Steady state concentrations are achieved within 7 days of once daily dosing. The mean accumulation ratio (R_ac) was 1.7 for C_max and 2.4 for AUC_0-24hr.

Absorption

Median vibegron T_max is approximately 1 to 3 hours.

Oral administration of a 75 mg vibegron tablet crushed and mixed with 15 mL of applesauce resulted in no clinically relevant changes in vibegron pharmacokinetics when compared to administration of an intact 75 mg vibegron tablet.

Effect of Food

No clinically significant differences in vibegron pharmacokinetics were observed following administration of a high-fat meal (53% fat, 869 calories [32.1 g protein, 70.2 g carbohydrate, and 51.1 g fat]).

Distribution

The mean apparent volume of distribution is 6304 liters. Human plasma protein binding of vibegron is approximately 50%. The average blood-to-plasma concentration ratio is 0.9.

Elimination

Vibegron has an effective half-life of 30.8 hours across all populations.

Metabolism

Metabolism plays a minor role in the elimination of vibegron. CYP3A4 is the predominant enzyme responsible for in vitro metabolism.

Excretion

Following a radiolabeled dose, approximately 59% of the dose (54% as unchanged) was recovered in feces and 20% (19% as unchanged) in urine.

Specific Populations

No clinically significant differences in the pharmacokinetics of vibegron were observed based on age (18 to 93 years), sex, race/ethnicity (Japanese vs. non-Japanese), mild (eGFR 60 to <90 mL/min/1.73 m²), moderate (eGFR 30 to <60 mL/min/1.73 m²), and severe (eGFR 15 to <30 mL/min/1.73 m²) renal impairment, or moderate (Child-Pugh B) hepatic impairment. The effect of more severe renal impairment (eGFR <15 mL/min/1.73 m²) with or without hemodialysis or severe (Child-Pugh C) hepatic impairment on vibegron pharmacokinetics was not studied.

Drug Interaction Studies

Clinical Studies

Digoxin: Concomitant administration of vibegron increased digoxin C_max and AUC by 21% and 11%, respectively.

Other Drugs: No clinically significant differences in vibegron pharmacokinetics were observed when used concomitantly with ketoconazole (P-gp and strong CYP3A4 inhibitor), diltiazem (P-gp and moderate CYP3A4 inhibitor), rifampin (strong CYP3A4 inducer), or tolterodine. No clinically significant differences in the pharmacokinetics of the following drugs were observed when used concomitantly with vibegron: tolterodine, tolterodine 5-hydroxy metabolite, metoprolol, combined oral contraceptive (ethinyl estradiol, levonorgestrel), or warfarin.

In Vitro Studies

Cytochrome P450 (CYP) Enzymes: Vibegron is a CYP3A4 substrate. Vibegron did not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A4. Vibegron did not induce CYP1A2, CYP2B6, or CYP3A4.

Transporter Systems: Vibegron is a P-gp substrate. Vibegron did not inhibit P-gp, BCRP, OATP1B1, OATP1B3, OAT1, OAT3, OCT1, OCT2, MATE1, or MATE2K at clinically relevant concentrations.