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Pharmacology: Mechanism of action: 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.
Pharmacodynamics: In three cystometric studies performed in patients with involuntary detrusor contractions, increased bladder capacity was demonstrated by an increased volume threshold for unstable contractions and diminished frequency of unstable detrusor contractions. These findings are consistent with an antimuscarinic action on the urinary bladder.
Pharmacokinetics: 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 level reached approximately 7 hours after administration of the prolonged-release tablets and steady state plasma levels are achieved by the sixth day of administration. Food had no effect on darifenacin pharmacokinetics during multiple-dose administration of prolonged-release tablets while Cmax is increase by 22% and Tmax was shortened by 3.3 hours.
Distribution: 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 L.
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 hydroxylation and N-dealkylation pathways are major circulating metabolites but none contribute significantly to the overall clinical effect of darifenacin.
Variability in Metabolism: 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 metabolizers. A few percent of the population have increased CYP2D6 enzyme levels (ultrafast metabolizers). The information previously mentioned applies to subjects who have normal CYP2D6 activity (extensive metabolizers) unless otherwise stated.
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 feces. Only a small percentage of the excreted dose was unchanged darifenacin (3%). Estimated darifenacin clearance is 40 L/hour. The elimination half-life of darifenacin following chronic dosing is approximately 13-19 hours.
Special Populations: Age: Darifenacin exposure at steady state was approximately 12-19% higher in volume in patients between 45 and 65 years of age compared to younger patients aged 18 to 44 years. Analysis data indicated a trend for clearance of Darifenacin to decrease with age (6% per decade relative to median age of 44).
Gender: A population pharmacokinetic analysis of patient data indicated that darifenacin exposure was 23% lower in males than females.
Race: The effect of race on the pharmacokinetics of Darifenacin has not been established.
Pediatric patients: The pharmacokinetics of darifenacin have not been established in the pediatric population.
Renal Impairment: A small study of subjects (n=24) 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.
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 daily to steady state. Mild hepatic impairment had no effect on the pharmacokinetics of darifenacin. However, protein binding of darifenacin was affected by moderate hepatic impairment. Unbound darifenacin exposure was estimated to be 4.7-fold higher in subjects with moderate hepatic impairment than subjects with normal hepatic function.
