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Darifenacin in the Treatment of Overactive Bladder

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Darifenacin in the Treatment of Overactive Bladder Drugs Aging 2004; 21 (13): 885-892 ADIS DRUG PROFILE 1170-229X/04/0013-0885/$31.00/0 © 2004 Adis Data Information BV. All rights reserved. Darifenacin In the Treatment of Overactive Bladder Katherine F. Croom and Gillian M. Keating Adis International Limited, Auckland, New Zealand Contents Abstract ....................................................................................885 1. Pharmacodynamic Profile ................................................................886 2. Pharmacokinetic Profile ..................................................................887 3. Therapeutic Efficacy .....................................................................887 4. Tolerability ...............................................................................890 5. Dosage and Administration ...............................................................891 6. Darifenacin: Current Status ................................................................891 Abstract Features and properties of controlled-release (CR) darifenacin (Enablex®, Emselex®) ▲ Darifenacin is a selective muscarinic M3-receptor antagonist that has been evaluated in clinical trials Indication in patients with overactive bladder syndrome Overactive bladder syndrome (OAB) using a controlled-release formulation. Mechanism of action ▲ In multicentre, randomised, double-blind trials in Muscarinic M3-receptor patients with OAB, darifenacin 7.5 or 15mg once antagonist daily for 12 weeks significantly reduced the fre- quency of urinary incontinence, frequency of mictu- Dosage and administration rition and frequency and severity of urgency versus Usual dosage in clinical trials 7.5 or 15 mg/day placebo. A significant difference from placebo was Route of administration Oral apparent 2 weeks after starting treatment. At a dos- age of 30mg once daily, darifenacin significantly Frequency Once daily prolonged warning time compared with placebo. Pharmacokinetic profile of CR darifenacin (steady state for ▲ Darifenacin 15mg once daily for 2 weeks was as 7.5 and 15mg once daily) effective as oxybutynin 5mg three times daily at Time to peak plasma ≈7h reducing the frequency of urinary incontinence and concentration frequency and severity of urgency in patients with Area under plasma 34 and 82 ng • h/mL OAB. concentration-time curve (7.5 ▲ Darifenacin was generally well tolerated in clinical and 15mg) trials. The most common adverse events were dry Bioavailability (7.5 and 15mg) 15% and 19% mouth and constipation. CNS tolerability appeared Elimination half-life (population 3.12h to be similar to that of placebo. analysis) ▲ Darifenacin had no adverse effect on cognitive Adverse events function in healthy elderly volunteers. Most common Dry mouth, constipation 886 Croom & Keating ● In vitro, darifenacin showed higher binding af- finity for the muscarinic M3 receptor than for other subtypes,[6,8,9,13] and greater antagonistic activity in H smooth muscle in which contraction is mediated by N M3 receptors than that in which contraction is medi- O O ated by M1, M2 or M4 receptors.[5,15,16] In human bladder tissue, the apparent antagonist potency of NH2 darifenacin was 8.72 and 8.40–9.34 in models using acetylcholine-[17] and carbachol-induced[14,18] mus- Darifenacin cle contraction (compared with 9.32 and 9.26–9.50 for atropine, a non-selective muscarinic receptor Overactive bladder syndrome (OAB) is a symp- antagonist). tom complex involving urinary urgency, with or ● In cystometry studies in rats[19] and minipigs,[20] without urge incontinence, generally accompanied both intravenous darifenacin (0.1–3.0 mg/kg in rats; by frequency and nocturia.[1] It is a common prob- 1–10 mg/kg in minipigs) and intravenous ox- lem, more so with increasing age,[2,3] with an overall ybutynin (a nonselective muscarinic receptor antag- prevalence of at least 16% in adults in the US and onist and an antispasmodic) [0.1–3.0 mg/kg in rats; Europe.[2,3] Anticholinergic (antimuscarinic) drugs 10–60 mg/kg in minipigs] caused dose-related de- are the mainstay of pharmacotherapy for OAB;[4] creases in micturition parameters, including peak however, currently available drugs are not specific micturition pressure. However, the dose required to for the bladder and cause adverse effects such as dry reduce peak micturition pressure by 50% was up to mouth, constipation, blurred vision or cognitive im- 14-fold lower for darifenacin than oxybutynin pairment.[4] (0.089 vs 0.83 mg/kg in rats, p < 0.05;[19] 3 vs 43 Recently, receptor-selective agents have been de- mg/kg in minipigs; statistical analysis not report- veloped to try and improve the tolerability of ther- ed[20]). ® apy. One such drug is darifenacin (Enablex , Em- ● Despite responses in both tissues being largely ® 1 selex ) , a muscarinic receptor antagonist that is mediated by M3 receptors, darifenacin showed se- [5-9] selective for the M3 receptor subtype. M3 recep- lectivity for bladder over salivary gland in vi- tors are found predominantly in smooth muscle and tro,[11,12,15] and functional selectivity for bladder exocrine glands; the urinary bladder contains both over salivary gland in one study in patients with M3 and M2 receptors, with the former having the detrusor instability,[21] and some,[19,22,23] but not [4] main role in detrusor contraction. A control- all,[10,12] in vivo animal studies. The latter finding is led-release oral formulation of darifenacin has been possibly as a result of the involvement of other evaluated in clinical trials. This article summarises receptor subtypes in salivary secretion, as suggested the pharmacology, efficacy and tolerability profile by the residual oral lubrication observed in pilocar- of darifenacin in patients with OAB. pine-treated M3 knockout mice.[24] ● In healthy male volunteers, darifenacin 7.5 and 1. Pharmacodynamic Profile 15mg once daily for 7 days produced only minor Darifenacin is a selective muscarinic M3-recep- changes in EEG activity, and had similar effects to tor antagonist.[5-9] Relevant data from human studies placebo on cognitive function tests (mediated by M1 [25] and animal models are discussed in this section. Six receptors) and heart rate (M2). studies[8,10-14] were reported in full, the remainder as ● Darifenacin also had no adverse effect on cogni- abstracts. tive function in elderly male and female volunteers 1 The use of trade names is for product identification purposes only and does not imply endorsement. © 2004 Adis Data Information BV. All rights reserved. Drugs Aging 2004; 21 (13) Darifenacin: Adis Drug Profile 887 (n = 129; aged 65–84 years) in a randomised, doub- ing of the dihydrobenzfuran ring and N-dealkyla- le-blind, placebo-controlled, 3-period crossover tion.[28] The hydroxylated metabolite was 50-fold study.[26] There was no significant difference be- less potent than the parent drug.[30] Excretion of tween controlled-release darifenacin 7.5 or 15mg darifenacin was rapid, with 77% of the total dose once daily for 2 weeks and placebo for memory being recovered within 48 hours.[28] Approximately scanning sensitivity, choice reaction time or word 44% of a dose was recovered from the faeces and recognition sensitivity (primary endpoints), nor for 58% from the urine, in both cases predominantly as simple reaction time, digit vigilance task speed and metabolites.[28] accuracy, memory scanning speed or word recogni- ● Darifenacin clearance was 40.2 L/h for a typical tion speed (secondary endpoints).[26] male CYP2D6 hom-EM.[27] Clearance was 31% lower in females than males.[27] The terminal elimi- 2. Pharmacokinetic Profile nation half-life of darifenacin was 3.12 hours in CYP2D6 hom-EM and 3.83 hours in poor Population pharmacokinetics for darifenacin (in- metabolisers.[27] travenous and oral, dose range 0.6–45mg) and its ● Pharmacokinetic analyses have indicated a trend hydroxylated metabolite were modelled using data for decreased clearance with advancing age (19% from 292 healthy volunteers and 45 patients with per decade, based on patients aged 60–89 years), OAB;[27] this section focuses on the controlled-re- and a 4.7-fold increase in exposure in the presence lease oral formulation where possible. An assess- of moderate hepatic impairment, but no effect on ment of the effect of cytochrome P450 (CYP) pharmacokinetics for mild hepatic impairment or isoenzyme 2D6 genotype on pharmacokinetics was varying degrees of renal impairment.[29] also included, given that darifenacin is metabolised ● by this isoenzyme. Steady-state pharmacokinetics of Coadministration of the CYP3A4 inhibitors ketoconazole and erythromycin increased darife- oral darifenacin 5mg three times daily in six healthy [27] male volunteers are discussed where appropriate.[28] nacin bioavailability to approximately 100%. Ketoconazole decreased darifenacin clearance by ● In the population analysis, median area under the 67.5%, whereas erythromycin had no effect on this plasma concentration-time curve at steady state for parameter. the controlled-release formulation of oral darife- nacin 7.5 and 15mg once daily was estimated to be 34 and 82 ng • h/mL, respectively.[27] Time to peak 3. Therapeutic Efficacy plasma concentration was ≈7 hours.[29] ● The bioavailability of darifenacin in a typical The clinical efficacy of oral controlled-release Caucasian male CYP2D6 homozygote-extensive darifenacin has been evaluated in several multicen- metaboliser (hom-EM, the more common genotype) tre, randomised, double-blind, parallel-group, place- was 15% and 19% after administration of con- bo-controlled studies in
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