Enablex Mechanism of Action

Pharmacotherapeutic group: Urinary antispasmodics. ATC code: G04B D10.
Pharmacology: Pharmacodynamics: Darifenacin is a selective muscarinic M3 receptor antagonist (M₃ SRA) in vitro. The M3 receptor is the major subtype that controls urinary bladder muscle contraction. It is not known whether this selectivity for the M3 receptor translates into any clinical advantage when treating symptoms of overactive bladder syndrome.
Cystometric studies performed with darifenacin in patients with involuntary bladder contractions showed increased bladder capacity, increased volume threshold for unstable contractions and diminished frequency of unstable detrusor contractions.
Treatment with ENABLEX administered at dosages of 7.5 mg and 15 mg daily has been investigated in four double-blind, Phase III, randomized, controlled clinical studies in male and female patients with symptoms of overactive bladder. As seen in Table 1 as follows, a pooled analysis of 3 of the studies for the treatment with both ENABLEX 7.5 mg and 15 mg provided a statistically significant improvement in the primary endpoint, reduction in incontinence episodes versus placebo. (See Table 1.)

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ENABLEX 7.5 mg and 15 mg doses significantly reduced both the severity and number of urinary urgency episodes and the number of micturitions, while significantly increasing the mean volume voided from baseline.
ENABLEX 7.5 mg and 15 mg were associated with statistically significant improvements over placebo in some aspects of quality of life as measured by the Kings Health Questionnaire including incontinence impact, role limitations, social limitations and severity measures.
For both doses of 7.5 mg and 15 mg, the percentage median reduction from baseline in the number of incontinence episodes per week was similar between males and females. The observed differences from placebo for males in terms of percentage and absolute reductions in incontinence episodes was lower than females.
The effect of treatment with 15 mg and 75 mg of darifenacin on QT/QTc interval was evaluated in a study in 179 healthy adults (44% male; 56% females) aged 18 to 65 for 6 days (to steady state). Therapeutic and supra-therapeutic doses of darifenacin resulted in no increase in QT/QTc interval prolongation from baseline compared to placebo at maximum darifenacin exposure.
Pharmacokinetics: Darifenacin is metabolized by CYP3A4 and CYP2D6. Due to genetic differences, about 7% of the Caucasians lack the CYP2D6 enzyme and are said to be poor metabolisers. A few percent of the population have increased CYP2D6 enzyme levels (ultrafast metabolisers). The following information applies to subjects who have normal CYP2D6 activity (extensive metabolisers) unless otherwise stated.
Absorption: Due to extensive first-pass metabolism darifenacin has a bioavailability of approximately 15% and 19% after 7.5 mg and 15 mg daily doses at steady state. Maximum plasma levels are reached approximately 7 hours after administration of the prolonged-release tablets and steady-state plasma levels are achieved by the sixth day of administration. At steady state, peak-to-trough fluctuations in darifenacin concentrations are small (PTF: 0.87 for 7.5 mg and 0.76 for 15 mg), thereby maintaining therapeutic plasma levels over the dosing interval. Food had no effect on darifenacin pharmacokinetics during multiple-dose administration of prolonged-release tablets.
Distribution: Darifenacin is a lipophilic base and is 98% bound to plasma proteins (primarily to alpha-1-acid-glycoprotein). The steady-state volume of distribution (Vss) is estimated to be 163 litres.
Metabolism: Darifenacin is extensively metabolized by the liver following oral administration.
Darifenacin undergoes significant metabolism by cytochrome CYP3A4 and CYP2D6 in the liver and by CYP3A4 in the gut wall. The three main metabolic routes are as follows: monohydroxylation in the dihydrobenzofuran ring; dihydrobenzofuran ring opening; and N-dealkylation of the pyrrolidine nitrogen.
The initial products of the hydrogenation and N-dealkylation pathways are major circulating metabolites but none contribute significantly to the overall clinical effect of darifenacin.
The pharmacokinetics of darifenacin at steady state are dose-dependent, due to saturation of the CYP2D6 enzyme.
Doubling the darifenacin dose from 7.5 mg to 15 mg result in a 150% increase in steady-state exposure. This dose-dependency is probably caused by saturation of the CYP2D6 catalysed metabolism possibly together with some saturation of CYP3A4-mediated gut wall.
Excretion: Following administration of an oral dose of ₁₄C-darifenacin solution to healthy volunteers, approximately 60% of the radioactivity was recovered in the urine and 40% in the faeces. Only a small percentage of the excreted dose was unchanged darifenacin (3%). Estimated darifenacin clearance is 40 litres/hour.
Special patient population: Gender: A population pharmacokinetic analysis of patient data indicated that darifenacin exposure was 23% lower in males than females (see Pharmacodynamics as previously mentioned).
Elderly patients: A population pharmacokinetic analysis of patient data indicated a trend for clearance to decrease with age (19% per decade based on Phase III population pharmacokinetic analysis of patients aged 60-89 years), see Dosage & Administration.
Paediatric patients: The pharmacokinetics of darifenacin have not been established in the paediatric population.
CYP2D6 poor metabolisers: The metabolism of darifenacin in CYP2D6 poor metabolisers is principally mediated by CYP3A4. In one pharmacokinetic study the steady-state exposure in poor metabolisms was 164% and 99% higher during treatment with 7.5 mg and 15 mg once daily, respectively. However, a population pharmacokinetic analyses of Phase III data indicated that on average steady-state exposure is 66% higher in poor metabolisers than in extensive metabolisers. There was considerable overlap between the ranges of exposures seen in these two populations (see Dosage & Administration).
Renal insufficiency: A study of subjects with varying degrees of renal impairment (creatinine clearance between 10 ml/min and 136 ml/min) given darifenacin 15 mg once daily to steady state demonstrated no relationship between renal function and darifenacin clearance (see Dosage & Administration).
Hepatic insufficiency: Darifenacin pharmacokinetics were investigated in subjects with mild (Child Pugh A) or moderate (Child Pugh B) impairment of hepatic function given darifenacin 15 mg once dally to steady state.
Mild hepatic impairment had no effect on the pharmacokinetics of darifenacin. Unbound darifenacin exposure was estimated to be 4.7-fold higher in subjects with moderate hepatic impairment than subjects with normal hepatic function (see Dosage & Administration).
Toxicology: Preclinical safety data: Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and carcinogenic potential.
Animal studies do not indicate direct or indirect harmful effects with respect to fertility, pregnancy, embryonal/foetal development. In peri and post natal studies in rats, dystocia, increased foetal deaths in utero, and toxicity to post natal development (pup body weight and development land marks) were observed at systemic exposure levels up to 11 times higher the expected clinical exposure.