Chemical formula: C₂₈H₃₀N₂O₂ Molecular mass: 426.55 g/mol PubChem compound: 444031
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.
Darifenacin is metabolised 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 information below applies to subjects who have normal CYP2D6 activity (extensive metabolisers) unless otherwise stated.
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.
Darifenacin is a lipophilic base and is 98% bound to plasma proteins (primarily to alpha-1-acidglycoprotein). The steady-state volume of distribution (Vss) is estimated to be 163 litres.
Darifenacin is extensively metabolised 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.
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 metabolism.
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. The elimination half-life of darifenacin following chronic dosing is approximately 13-19 hours.
A population pharmacokinetic analysis of patient data indicated that darifenacin exposure was 23% lower in males than females.
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).
The pharmacokinetics of darifenacin have not been established in the paediatric population.
The metabolism of darifenacin in CYP2D6 poor metabolisers is principally mediated by CYP3A4. In one pharmacokinetic study the steady-state exposure in poor metabolisers 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.
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.
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.
Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and carcinogenic potential. There were no effects on fertility in male and female rats treated at oral doses up to 50 mg/kg/day (78 times the AUC0-24h of free plasma concentration at maximum recommended human dose [MRHD]). There were no effects on reproductive organs in either sex in dogs treated for 1 year at oral doses up to 6 mg/kg/day (82 times the AUC0-24h of free plasma concentration at MRHD). Darifenacin was not teratogenic in rats and rabbits at doses up to 50 and 30 mg/kg/day, respectively. At the dose of 50 mg/kg/day in rats (59 times the AUC0-24h of free plasma concentration at MRHD), delay in the ossification of the sacral and caudal vertebrae was observed. At the dose of 30 mg/kg/day in rabbits (28 times the AUC0-24h of free plasma concentration at MRHD), maternal toxicity and foetotoxicity (increased post implantation loss and decreased number of viable foetuses per litter) were observed. 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 the AUC0-24h of free plasma concentration at MRHD.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.
