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Darifenacin: a Selective M3 Muscarinic Receptor Antagonist for the Treatment of Overactive Bladder

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Darifenacin: a Selective M3 Muscarinic Receptor Antagonist for the Treatment of Overactive Bladder DRUG PROFILE Darifenacin: a selective M3 muscarinic receptor antagonist for the treatment of overactive bladder Phillip P Smith, Overactive bladder is a common and distressing disorder that imposes significant financial H Henry Lai & and quality-of-life costs. The current therapeutic paradigm aims to decrease detrusor Rodney A Appell† overactivity via blockade of bladder M muscarinic receptors, the primary cholinergic †Author for correspondence 3 Division of Voiding receptors responsible for detrusor contraction. However, systemic antimuscarinic adverse Dysfunction & Female effects, such as dry mouth and constipation, limit the tolerability of antimuscarinic Urology, Scott Department of treatment. Therefore, a uroselective M3 receptor antagonist would be considered optimal Urology, Baylor College of ® Medicine, 6560 Fannin, therapy for overactive bladder. Darifenacin (Enablex ) is the most recent antimuscarinic Suite 2100, Houston, drug approved for the treatment of overactive bladder. It demonstrates M3 receptor TX 77030, USA selectivity, but is not M3 specific. Despite animal data suggesting uroselectivity, it is not Tel.: +1 713 798 6115 sufficiently uroselective in therapeutic use. While effective in reducing symptoms related Fax: +1 713 798 8185 [email protected] to overactive bladder, dry mouth and constipation remain common. There are no comparative trials comparing darifenacin with existing agents, therefore it is not known if darifenacin represents an improvement over existing agents. Overactive bladder (OAB) is characterized by the receptors are not unique to the bladder, adverse lower urinary tract symptoms of urgency, urge effects would be expected from blockade of mus- incontinence, urinary frequency and nocturia. It carinic receptors in other organ systems. The sys- is a common and distressing problem, estimated temic adverse effects of antimuscarinic agents are to afflict 15–17% of adult men and women in attributed to the lack of organ specificity to the the USA [1,2]. OAB is associated with an M3 muscarinic receptors in the bladder (urose- impaired quality of life, depression and poor lectivity) and to the indiscriminate blockade of sleep [1]. The economic burden is difficult to other muscarinic receptor subtypes (M1, M2, M4 quantitate, but is estimated at US$9.1 billion and M5). M1 receptors are abundant in the cere- (year 2000 values) annually [2]. The etiology of bral cortex, hippocampus and neostriatum [6] the disorder is unknown and most cases are and may be important for cognitive functions, regarded as idiopathic. such as memory, learning and attention [7–9]. The therapeutic model used in the treatment CNS M1 blockade impairs cognition [3]. M1 and of OAB is primarily concerned with suppressing M3 receptors are both involved in salivary secre- undesired activity of the detrusor muscle. The tion [10] and indiscriminate blockade of M1 and detrusor muscle contracts in response to the M3 salivary receptors causes significant dry release of acetylcholine, via activation of mus- mouth. Inhibition of M3 muscarinic receptors in carinic cholinergic receptors. Five subtypes of the the gastrointestinal tract and the eye also causes muscarinic receptor have been identified: M1, constipation and blurred vision, respectively. M2, M3, M4 and M5. The detrusor expresses Finally, M2 receptors play a role in modulating receptor subtypes M2 and M3 in a 2:1 ratio [3]. heart rate and cardiac output [11]. Interference Activation of the M3 receptors by acetylcholine with cardiac M2 receptor function may be associ- released by efferent terminals results in phospho- ated with EKG changes, such as bradycardia and inositide hydrolysis, leading to muscle contrac- arrhythmias [3]. tion [4,5]. The M2 receptors are not associated These significant adverse effects limit the with phosphoinositide accumulation in the ability to dose-titrate antimuscarinic drugs to detrusor [4] and, therefore, the M receptors are an optimal therapeutic dose. Thus, an agent Keywords: darifenacin, 3 M3 muscarinic antagonist, thought to be primarily responsible for detrusor that selectively targets the bladder M3 recep- overactive bladder contraction [3]. tors and so minimizes adverse effects might be All antimuscarinic drugs currently available expected to offer the best overall therapeutic for the treatment of OAB block the bladder effect [12]. Animal studies have demonstrated a M3 receptors, and by this means are thought to greater specificity of darifenacin to the Future Drugs Ltd decrease motor overactivity. Since muscarinic M3 receptor compared with other muscarinic 10.1586/14750708.3.6.723 © 2006 Future Drugs Ltd ISSN 1475-0708 Therapy (2006) 3(6), 723–732 723 DRUG PROFILE – Smith, Lai & Appell subtypes, as well as M3 uroselectivity, suggesting to M3 receptors than to M1 receptors (Kd =1.6 its potential as an improvement over existing vs 0.33) and minimal binding to M2, M4 and antimuscarinic agents. M5 receptors [13]. Darifenacin demonstrates enhanced binding at the M3 receptor compared Darifenacin with other muscarinic subtypes by a ratio of 9, Darifenacin hydrobromide is the most recent addi- 59, 60 and 12, when compared with M1, M2, tion to the antimuscarinic formulary intended for M4 and M5 subtypes, respectively [15]. use in the treatment of OAB. Antimuscarinics cur- Darifenacin binds competitively to the M3 mus- rently approved for use in the USA for OAB carinic receptors and has a dissociation constant ® include oxybutynin chloride (Ditropan and for the M3 receptors greater than tolterodine and generic), tolterodine tartrate (Detrol®), trospium oxybutynin [16,17]. In human bladder strips, chloride (Sanctura®), solefenacin succinate (Vesi- darifenacin inhibited carbachol-induced con- ® care™) and darifenacin (Enablex ). Oxybutynin is tractions, but did not inhibit KCl- or CaCl2- available in immediate-release oral, extended- induced contractions [16]. Thus, its anticontrac- release oral and transdermal formulations. Toltero- tile action is consistent with M3 blockade rather dine is available in immediate-release and than action as a calcium channel antagonist [18]. extended-release oral formulations. Trospium chlo- In animal in vitro and in vivo studies, ride is currently only available as an immediate- darifenacin demonstrates greater effect on blad- release agent, but solefenacin and darifenacin are der M3 receptors than in other tissues, such as the both available as extended-release oral forms. salivary gland. Darifenacin was found to be more Darifenacin is the first M3-selective receptor effective on smooth muscle preparations from antagonist [13]. It was approved by the US FDA guinea pig ileum and bladder than on the salivary for the treatment of overactive bladder in Decem- glands. It is as potent as atropine at inhibiting ber 2004, and was brought to market in February carbachol-induced contractions in smooth mus- 2005. It is marketed in the USA as Enablex cle but has a sixth of the potency of atropine in (Novartis Pharmaceuticals, Proctor and Gamble the salivary glands [14]. In beagle dogs, Pharaceuticals). It is available in extended-release darifenacin inhibited induced jejunal motility oral tablets containing either 7.5 or 15 mg of similar to atropine, with significantly less effect darifenacin hydrobromide as the active agent. than atropine at inhibiting salivation [19]. In a mouse model, darifenacin induced tremor (an Chemistry M1 receptor-mediated effect) and inhibited sali- Chemically, darifenacin is (S)-2-{1-[2-(2,3-dihy- vation less than atropine, and was equipotent to drobenzofuran-5-yl)ethyl]-3-pyrrolidinyl}-2,2- atropine at inhibiting smooth muscle contrac- diphenylacetamide and has a molecular weight tion [18]. It was compared with other anticholin- of 507.5. The structural formula is shown in ergic drugs in anesthetized dog experiments Figure 1. It is a white crystalline powder. It is only evaluating the effect on pelvic nerve-stimulated moderately stereoselective, the R enantiomer bladder contractions, trigeminal nerve stimu- being slightly less potent in guinea pig ileum lated salivation and heart rate changes. These preparations [14]. data demonstrate that the selectivity of darifenacin for bladder over salivary glands is a Pharmacology factor of ten, roughly twice that of oxybutynin, Darifenacin is a M3-selective receptor antagonist. tolterodine and propiverine, as shown in Table 1 In vitro studies using Chinese hamster ovary [20]. No human in vitro studies have specifically (CHO) cells demonstrate a sixfold greater affinity investigated the relative bladder M3 specificity demonstrated by animal studies. Figure 1. Darifenacin hydrobromide. Pharmacokinetics Darifenacin is well absorbed from the gut [21], Ph primarily from the colon in the prolonged-release form available for clinical use [22]. A study of Ph N pooled data from 337 patients in Phase I and II trials described the pharmacokinetics of several O NH 2 different formulations of the drug [23]. The drug O was given orally (1–45 mg) in immediate- and extended-release forms, as well as intravenously 724 Therapy (2006) 3(6) Darifenacin – DRUG PROFILE Table 1. ID50 values of various antimuscarinic drugs in various tissues. Antimuscarinic drug Bladder (ID50 value) Salivary (ID50 value) Heart rate (ID50 value) Darifenacin 6.7 67 >100 Oxybutynin 30 123 >300 Tolterodine 37 185 265 Propiverine 1139 4755 >10000 From [14]. ID50: 50% inhibitory value. (0.6–6 mg). The half-life of absorption increased fluconazole. Plasma concentrations of imi- as the release duration was
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