Vibegron

Vibegron is a selective and potent human beta-3 adrenergic receptor agonist over β1-AR and β2-AR. Activation of the beta-3 adrenergic receptor located in the bladder detrusor muscle increases bladder capacity by relaxing the detrusor smooth muscle during bladder filling.

Absorption

Mean vibegron C_max and AUC increased in a greater than dose-proportional manner up to 600 and 400 mg after single and repeated dose, respectively. Steady state concentrations are achieved within 7 days of once daily dosing. The mean accumulation ratio (Rac) was 1.7 for C_max and 2.4 for AUC_0-24hr. Median vibegron T_max is approximately 1 to 3 hours.

Oral administration of vibegron 75 mg film-coated 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 vibegron 75 mg film-coated tablet. Therefore, vibegron can be crushed for administration in soft food.

Effect of food

Co-administration of a 75 mg tablet with a high-fat meal reduced vibegron C_max and AUC by 63% and 37%, respectively. The effect of food appeared to be smaller at steady state (unchanged AUC and 30% lower C_max). In the phase 3 studies demonstrating efficacy and safety, vibegron was administered with or without food. Therefore, vibegron can be taken with or without food.

Distribution

The mean apparent volume of distribution following oral administration is 9 120 litres. Human plasma protein binding of vibegron is approximately 50%. The average blood-to-plasma concentration ratio is 0.9.

Biotransformation

Vibegron is metabolised via oxidation and direct glucuronidation but metabolism is not a major route of elimination. Vibegron is the major circulating component following a single dose of ¹⁴C-vibegron. One major metabolite was observed in human plasma being a phase II glucuronide representing 12 to 14% of total exposure. All the recombinant UGT enzymes evaluated in vitro demonstrated some metabolism of vibegron (mainly UGT1A3, UGT1A4, UGT1A6, UGT2B10, UGT2B15). Although in vitro studies suggest a role for CYP3A4 in the oxidative metabolism of vibegron, in vivo results indicate that these isozymes play a limited role in the overall elimination.

Elimination

The mean terminal half-life (t_½) values following multiple-dose administration ranges from 59 to 94 hours in young and elderly subjects, and the effective half-life is approximately 31 hours across all populations.

Following the oral administration of 100 mg ¹⁴C-vibegron to heathy volunteers, approximately 59% of the radiolabeled dose was recovered in faeces and 20% in urine. Unchanged vibegron accounted for the majority of the excreted radioactivity (54 and 19% of the radiolabelled in faeces and urine, respectively). Most of the dose recovered in faeces is likely unabsorbed substance. Urinary excretion of unchanged substance is a major route of elimination (around 50% of the absorbed vibegron). Biliary excretion of unchanged substance may also contribute to the elimination while hepatic metabolism appears to play a minor part.

Renal impairment

Relative to volunteers with normal renal function (GFR ≥ 90 mL/min), administration of 100 mg single dose of vibegron increased mean C_max and AUC by:

• 1.6- and 2.1-fold, respectively in volunteers with mild renal impairment (60 ≤ GFR < 90 mL/min)
• 2.0- and 1.6-fold, respectively in volunteers with moderate renal impairment (30 ≤ GFR < 60 mL/min)
• 1.8- and 1.2-fold, respectively in volunteers with severe renal impairment (GFR < 30 mL/min)

No dose adjustment for vibegron is recommended for patients with mild, moderate, or severe renal impairment (15 mL/min < GFR < 90 mL/min and not requiring dialysis). Vibegron has not been studied in patients with end stage renal disease (GFR < 15 mL/min with or without haemodialysis) and is therefore not recommended in these patients.

Hepatic impairment

Relative to volunteers with normal hepatic function, administration of 100 mg single dose of vibegron increased mean C_max and AUC by 1.3- and 1.3-fold, respectively in volunteers with moderate hepatic impairment (Child-Pugh Class B).

No dose adjustment for vibegron is recommended for patients with mild to moderate hepatic impairment (Child-Pugh A and B). Vibegron has not been studied in patients with severe hepatic impairment (Child-Pugh C) and is therefore not recommended in this patient population.

Paediatric population

No pharmacokinetic data are available in children below 18 years of age.

Other special populations

No clinically significant differences in the pharmacokinetics of vibegron were observed based on age (studied range: 18 to 93 years), gender or race/ethnicity.

Weight (studied range: 39 to 161 kg) had a modest effect on clearance and central volume of distribution in the population pharmacokinetic analysis. The increase in vibegron exposures resulting from differences in weight are not considered clinically significant.

Vibegron showed 9 and 78-times lower in vitro β3-AR potency for rabbits and rats, respectively, when compared to humans. Therefore, safety margins for potential β3-AR-mediated effects on development or reproduction are accordingly lower than for non-β3-AR-related effects.

In animal studies no effects on embryo-foetal development were observed following oral administration of vibegron during the period of organogenesis at exposures (AUC) approximately 275-fold and 285-fold greater than clinical exposure at the recommended human dose (RHD) of 75 mg/day vibegron, in rats and rabbits, respectively. Delayed foetal skeletal ossification and reduced foetal body weights were observed in rabbits at approximately 898-fold clinical exposure (AUC) at the RHD, in the presence of maternal toxicity. In rats treated with vibegron during pregnancy and lactation, no effects on offspring were observed at 89-fold clinical exposure at the RHD. Developmental toxicity was observed in offspring at approximately 458-fold clinical exposure (AUC) at the RHD, in the presence of maternal toxicity.

When a single oral dose of radiolabeled vibegron was administered to postnatal nursing rats, radioactivity was observed in milk.

No effects on fertility were observed in female or male rats at doses up to 300 mg/kg/day, associated with systemic exposure (AUC) at least 275-fold higher than in humans at the RHD of 75 mg/day. General toxicity, decreased fecundity, and decreased fertility were observed in female rats at 1 000 mg/kg/day, associated with estimated systemic exposure 1 867-fold higher (AUC) than in humans at the RHD of 75 mg/day.