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

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 extended. The drug is pramine may be elevated by the concurrent use completely absorbed, with the immediate-release of darifenacin [22]. form being primarily in the upper gastrointestinal (GI) tract, whereas the extended-release formula- Clinical efficacy tion reaches the lower gut and, thus, is exposed to Clinical efficacy of antimuscarinic drugs in treat- less metabolic activity in the first pass. Relative ing OAB has been hampered by frequent adverse bioavailability of the prolonged-release form is effects, such as dry mouth, constipation, blurred approximately twice that of the immediate- vision, drowsiness and cognitive changes in eld- release form [22]. Absolute bioavailability of the erly patients [26]. These dose-related adverse prolonged-release form of the drug is estimated effects limit the maximum therapeutic dose that to be 15.4% for the 7.5 mg dose and 18.6% for can be tolerated and are often bothersome the 15 mg tablets in cytochrome P450 enough to cause patient nonadherence, subopti- (CYP)2D6 extensive metabolizers. mal dosing and drug discontinuation. For The volume of distribution of darifenacin instance, only 18–22% of patients prescribed has been calculated to be 165–276 l in healthy with immediate-release oxybutynin remained on volunteers [22]. In humans, the drug is 98% the medication after 6 months owing to intolera- protein bound and its primary metabolite is ble adverse effects [27,28]. Since OAB is a chronic 87% bound. The metabolite has 11% of the debilitating condition requiring long-term treat- activity of the drug. Correcting for the in vivo ment to alleviate the symptoms, it is important protein binding, the metabolite is 50-fold less that the anticholinergic medication are not only potent than the parent drug [21]. It is a effective but also well tolerated. lipophilic molecule, thus some degree of CNS While darifenacin preferentially blockades M3 penetration might be expected; however, there receptors versus other muscarinic subtypes, it is are no data regarding specific distribution of not completely bladder M3 specific. The in vitro the drug in human tissues [22]. animal data demonstrating relative uroselectivity The drug undergoes hepatic metabolism via has not been confirmed by in vivo human stud- three main pathways: monohydroxylation, oxi- ies, as suggested by the results obtained by Rosa- dative dihydrobenzfuran ring opening and rio [24]. Although the drug may not be N-dealkylation. There are no marked species uroselective, it has less indiscriminate blockade differences in metabolism [21]. Darifenacin is a of other muscarinic receptor subtypes. The theo- CYP pathway substrate that is metabolized via retical advantages are that there may be less cog- CYP2D6 and CYP3A4 pathways [22]. The nitive changes (less CNS M1 blockade), fewer CYP3A4 inhibitors ketoconazole and erythro- cardiovascular effects (less M2 blockade) and less mycin increase the bioavailability to 100% and dry mouth (less salivary gland M1 blockade [10]). decrease the exposure to metabolites [21]. Clear- Rosario and colleagues randomized 18 patients ance of the drug was found to be 40.2 l/h and to receive either darifenacin or placebo [24]. Uro- ketoconazole decreased clearance by 67.5%. dynamic and salivary flow testing was used to The clearance is 31% lower in females and 10% study the 10 and 2.5 mg doses. Salivary flow was lower at night [23]. The drug is excreted as its reduced by the 10 mg dose, whereas 2.5 mg had metabolites, approximately 60% via urine and no effect on salivary flow. The volume threshold 40% via feces. Food does not affect the for detrusor activity was increased by the 10-mg pharmacokinetics of darifenacin. Hepatic dose, with no change in the amplitude of overac- impairment increases plasma concentrations, as tivity contractions. The 2.5-mg dose did not alter do the drugs ketoconazole, erythromycin and urodynamic parameters [24]. In a Phase II study of

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darifenacin, patients with detrusor activity were than 50% reduction in weekly incontinent epi- monitored by continuous ambulatory urodynam- sode [32,33]. An even smaller percentage (34%) ics. Multiple doses were well tolerated and of patients reported greater than 50% reduction reduced the total number, maximum amplitude in weekly urgency episode [33]. No improve- and duration of detrusor overactivity-associated ment in nocturia was noted. One placebo-con- contractions [25]. trolled study demonstrated an improvement in Darifenacin (7.5 or 15 mg/day) is more warning time of 4.3min compared with pla- effective than placebo in alleviating OAB cebo with darifenacin 30 mg (two- to four- symptoms. Results from several large Phase III, times the recommended dosage) [34]. Another randomized, multicenter, double-blind, pla- placebo-controlled study failed to demonstrate cebo-controlled, parallel-group trials are sum- any improvement in warning time with marized in Table 2 [29–33]. Patient age in these darifenacin 15 mg [30], although these studies trials covered a wide range (20–93 years), but were performed to evaluate warning time as a the mean ages were typically in the high 50s. possible OAB outcome parameter, and were not Approximately a third of patients are aged over intended as efficacy trials for darifenacin. 65 years. Most patients were white (>90%) and The clinical response was dose responsive in females (>80%), who complained of typical placebo-controlled studies. A small (∼10%) OAB symptoms. Both naive patients who had improvement in the median number of weekly never received prior antimuscarinic drugs and incontinent episodes was noted when the dosage those who had were included in these studies. was increased from 7.5 to 15 mg/day [29,31,33]. Fur- The improvements in weekly incontinence epi- ther improvement (∼20%) in the mean number of sode and weekly urgency episode were consist- incontinent episodes was noted when the dosage ent among the studies. However, the was increased from 15 to 30 mg/day [35]. The improvements were only moderate. At the onset of efficacy was rapid. Two-thirds of the maximum recommended dosage (15 mg/day), therapeutic benefits were already experienced by only 62–70% of patients experienced a greater the second week of treatment [29,32]. Efficacy

Table 2. Clinical efficacy of darifenacin versus placebo or oxybutynin. Study Efficacy Reduction in median number of weekly Reduction in median number of weekly Ref. reported incontinent episodes (%) urge episodes (%) at Darifenacin (mg) Placebo Oxybutynin Darifenacin (mg) Placebo Oxybutynin (weeks) 7.5 15 30 5 mg t.i.d. 7.5 15 30 5mg t.i.d. Haab et al. 2435334 [29] (2004) 12 69 72 51 29 29 13 Zinner et al. 12 67 47 22* 18* [30] (2006) Steers et al. 24329 144 [32] (2005) 12 63‡ 48 28‡ 11 Chapple 12 68 77 55–58 29 29 14–17 [33] et al. (2005) Hill et al. 12 69 77 77 46 29 27 33 16 [31] (2006) Zinner 2 46 57 28 54 15 18 6 13 [35] et al§ (2005) Habb et al.¶ 2 years 84¶ 56¶ [36] (2006) *The 15 mg darifenacin result was not statistically significant from that of placebo. ‡By 12 weeks, patients were taking either 7.5 or 15 mg/day of darifenacin in this dose-titration study. §Mean (not median) results. ¶Extension study of [29,32], patients were taking either 7.5 or 15 mg/day. t.i.d.: Three-times daily.

726 Therapy (2006) 3(6) Darifenacin – DRUG PROFILE

continued to improve at 12 weeks when the tolterodine studies [37–39]. The placebo effect of studies concluded. Habb and colleagues recently darifenacin trials (∼50%) was significantly published the results of a multicenter, noncom- higher than that of other antimuscarinic trials parative, open-label extension study in which (∼30%), therefore the delta-efficacy (defined as patients chose to take either 7.5 or 15 mg/day drug effect minus placebo effect) of darifenacin after they had finished the 12-week feeder stud- may actually be smaller. Whether the disparity ies [29,32,36]. At a median follow-up of 2 years (the of delta-efficacy represents a true difference in longest yet published for a trial of a controlled- drug efficacy or reflects different experimental release antimuscarinic), the efficacy of designs remains to be determined. darifenacin was maintained in the 66% of patients who completed the extension study (a Adverse effects & tolerability 84% decline in the number of incontinent epi- Despite a good level of efficacy in OAB patients, sodes per week, compared with feeder study dry mouth and constipation continued to baseline; p < 0.001) (Table 2). Good clinical plague a significant number of patients taking response has been reported in men and women darifenacin. In Phase III, randomized, multi- over a wide range of ages, although patients with center, double-blind, parallel-group, placebo- OAB secondary to interstitial cystitis, anterior controlled trials lasting 1–12 weeks, the inci- vaginal prolapse (cystocele), bladder outlet dences of dry mouth and constipation for obstruction, prostatic enlargement or mixed darifenacin were higher than that of placebo incontinence with significant stress component (p > 0.05) (Table 3) [29–33,40–42]. These adverse have not been studied specifically since these are effects were mild to moderate, as they were rarely common exclusion criteria in OAB trials [29–33]. severe enough to cause discontinuation of the There are no well-designed, randomized, medication or dosage reduction (0–2.3% for dry comparative studies comparing darifenacin with mouth, 0–2.3% for constipation) [30–33]. The currently marketed antimuscarinic drugs. The incidence of dry mouth of darifancin was dose only published report that compared darifenacin dependent [41]. Despite a high incidence of con- (15 or 30 mg/day) to immediate-release oxybu- stipation, the percentage of darifenacin patients tynin (5 mg three-times daily) was a four-way using laxatives or stool softeners was similar to crossover study (a suboptimal experimental placebo (30% in the darifanacin 15 mg group, design) that was too short in duration (2 weeks 25% in the placebo group) [33], suggesting that for each drug) and enrolled too few patients the drug-induced constipation (or even its (76 total in all arms) to really address the differ- definition in the studies) may not be severe. ence in efficacy [35]. Plus, it is not fair to com- A 2-year, open-label extension study demon- pare darifenacin with oxybutynin 5 mg three- strated that darifenacin (7.5 or 15 mg/day) was times daily since the former is an extended- well tolerated in the long term [36]. At median release formulation while the latter is not. Nev- follow-up of 2 years, 66% of patients completed ertheless, in that particular study [35], the extension study, while 9% discontinued due darifenacin 15–30 mg had similar efficacy as to adverse effects (most of the withdrawals were oxybutynin 5 mg three-times daily (46–57% vs during the first 3 months of the extension). A 54% reduction in weekly incontinent episodes, total of 23% of patients reported dry mouth, p > 0.05; 15–18% reduction in weekly urgency although only 1.3% were severe enough to cause episodes, p > 0.05). There are currently no ran- discontinuation. Constipation was reported by domized studies that compare darifenacin with 20% of patients, yet only 2.4% withdrew due to any of the currently routinely used antimus- constipation. Use of fiber supplements, stool sof- carinics (extended-release oxybutynin, tolterod- teners or laxatives was initiated by only 5.6% of ine, trospium chloride or solefenacin). Without patients during the study. Analysis of bowel- well-designed head-to-head studies, one simply habit questionnaires revealed that the reporting do not know whether darifenacin is more effec- of constipation was related to minor changes in tive than other antimuscarinic drugs. In the bowel habit rather than true constipation. absence of head-to-head studies, adjusting drug Three studies have compared the adverse effect response rates for the placebo response (so-called profiles of darifenacin with either immediate- ‘delta-efficacy’ or ‘effect-size’) may be one release [35,41] or extended-release oxybutynin [42]. method of comparing the efficacy data from pla- Zinner and colleagues randomized 76 patients to cebo-controlled darifenacin studies [29–33] with receive 2 weeks of darifenacin 15 mg, darifenacin those from placebo-controlled oxybutynin or 30 mg, oxybutynin 5 mg three-times daily or www.future-drugs.com 727 DRUG PROFILE – Smith, Lai & Appell

Table 3. Incidence of adverse effects of darifenacin versus placebo or oxybutynin. Study Side Dry mouth (%) Constipation (%) Ref. effects at Darifenacin (mg) Placebo Oxy Darifenacin (mg) Placebo Oxy (weeks) 7.5 15 30 7.5 15 30 Haab et al. 12 19 31 9 14 14 7 [29] (2004) Zinner et al. 12 29 6 18 5 [30] (2006) Steers et al. 12 19* 21* [32] (2005) Chapple et al. 12 20 35 8 15 21 6 [33] (2005) Hill et al. 12 23 40 60 6 16 25 28 5 [31] (2006) Kay et al. 7 days 30 48 13 [40] (2005) Kay et al. 3 27 12 40 (20 mg 20 2 4 (20 mg [42] (2006) ER od)‡ ER od)‡ Lipton et al. 2 7 9 3 13 (5 mg 8 12 9 13 (5 mg [41] (2005) IR t.i.d.)§ IR t.i.d.)§ Zinner et al. 2 13 30 5 36 (5 mg 10 21 3 8 (?? mg [35] (2005) IR t.i.d.)§ IR t.i.d.)§ Habb et al.¶ 2 years 23 20 [36] (2006) *By 12 weeks, patients were taking either 7.5 mg or 15 mg daily of darifenacin in this dose-titration study. ‡Oxybutynin 20 mg extended-release (ER) daily (od). §Oxybutynin 5 mg immediate-release (IR) thrice daily (t.i.d.). ¶Open extension study of [29,32], patients were taking either 7.5 or 15 mg daily. ER: Extended release; IR: Immediate release; od: Once daily; Oxy: Oxybutynin; t.i.d.: Three-times daily.

placebo in a four-way crossover study [35]. The with oxybutynin 5 mg three-times daily; group showed that the incidence of dry mouth p > 0.05) [41]. Also, no differences in constipation for darifenacin 15 mg (13.1%) was statistically rates were noted (p > 0.05). In the third study equivalent to that of placebo (4.9%; p > 0.05), (randomized, double-blind, non-crossover), Kay but much less than that of either darifenacin and colleagues demonstrated that the incidence 30 mg (34.4%; p < 0.05) or immediate-release of dry mouth was lower in the darifenacin 15 mg oxybutynin (36.1%; p < 0.05). The dry mouth group than in the extended-release oxybutynin adverse effect of darifenacin 30 mg was as poor as group after 3 weeks of treatment (27% with that of oxybutynin 5 mg three-times daily darifenacin 15 mg, 40% with oxybutynin 20 mg (p > 0.05). The incidence of constipation of low- and 12% with placebo) [42]. The constipation dose, darifenacin 15 mg (13.1%) was statistically rate of darifenacin in that trial (20%) was actu- similar to that of oxybutynin 5 mg three-times ally higher than that of oxybutynin (4%) and daily (8.2%; p > 0.05) and placebo (3.3%; placebo (2%). p > 0.05). The incidence of high dose, None of the studies in the aforementioned darifenacin 30 mg (21.3%) was significantly published literature answered the question as to worse than that of 5 mg three-times daily oxybu- whether darifenacin causes less dry mouth or con- tynin or placebo (p < 0.05). Lipton and col- stipation than other antimuscarinic drugs. All of leagues demonstrated no differences in the these studies [35,41,42] were suboptimal since: incidence of dry mouth between the darifenacin • The study durations were too short groups and the immediate-release oxybutynin (2–3 weeks); group in a three-period crossover study (4.2% • They were complex crossover studies rather with darifenacin 3.75 mg, 6.8% with darifenacin than head-to-head, randomized, blinded 7.5 mg, 9.2% with darifenacin 15 mg, 12.7% clinical trials;

728 Therapy (2006) 3(6) Darifenacin – DRUG PROFILE

• The sampling sizes were too small to achieve (mean difference: -0.06, p > 0.05). By contrast, statistical power; oxybutynin resulted in memory impairment, with significantly lower Name-Face Association • The studies were not designed to compare Test scores than placebo and darifenacin (mean adverse effects as primary end points. differences: -1.30 and -1.24, p > 0.05). Addi- No other trials have compared darifenacin tional tests of delayed recall indicated signifi- with tolterodine, trospium chloride or cant memory impairment with oxybutynin solefenacin. Head-to-head, randomized, versus placebo, whereas darifenacin was similar blinded, comparative studies of longer duration to placebo. While statistical difference has been (>12 weeks) must be performed to determine if reached, it is unclear whether it translates to darifenacin offers a better tolerability profile clinical significance. CNS adverse effects have than other antimuscarinic agents. Given the lack not been a significant clinical issue when other of demonstrated human uroselectivity of antimuscarinic drugs were used. Even if darifenacin, one would not expect darifancin to darifenacin offers marginal improvement over have less dry mouth or constipation than other other antimuscarinics, if at all, it is unclear if antimuscarinics. the difference is clinically significant. One potential advantage of M3 receptor selec- Cardiac adverse effects were very rare with tivity of darifenacin over other antimuscrinics is darifenacin (up to 1.5%) [32] with the incidence less cognitive changes owing to less CNS M1 being similar to that of placebo [33,44]. No signifi- blockade. Theoretically, CNS adverse effect may cant changes in heart rate, heart rate variability, be an issue in the elderly since: electrocardiogram (ECG) and vital signs were • They often have other comorbidities that noted in several studies [40,41]. In Haab’s study, one might predispose them to neurocognitive patient out of 344 who took darifenacin 7.5 mg problems; reported second-degree atrioventricular heart block [29]. In this patient, the heart block was a • They may take multiple medications that pre-existing condition and it was unclear whether exacerbate the adverse effects on cognition; it was associated with darifenacin usage. No • Most antimuscarinic drugs, including adverse cardiac events were noted when twice the darifenacin, undergo hepatic-cytochrome recommended daily dose (30 mg) was used [31]. metabolism and are subject to altered Despite the importance of M3 receptors in vis- metabolism due to polypharmacy. ual accommodation, darifenacin is not associ- Darifenacin did not cause cognitive adverse ated with visual near-point change [40] or blurred effects in young [40] or elderly patients [41,42] vision [29,35]. when used at 15 [29] or 30 mg (twice the recommended dose) [31,35]. The lack of CNS adverse Conclusions & outlook effects may be attributed to: Darifenacin is the latest addition to the • No crossing of the blood–brain barrier (in ani- antimuscarinic armentarium for the treatment mal studies) due to darifenacin’s moderate of overactive bladder. It is the first M3-selective lipophilicity, large molecular size, polarity and receptor antagonist, although it is not com- active efflux out of the CNS through the pletely M3 specific. Animal data suggest it may be more uroselective than other anticholiner- P-glycoprotein pumps [22,43]; gics. Despite these theoretical advantages, it has •Its M3 receptor selectivity with less interfer- not demonstrated a conclusive therapeutic effi- ence of CNS M1 activity that mediates cogni- cacy or tolerability profile above and beyond tive functions, such as memory, learning and existing antimuscarinic agents, due in part to its attention [7–9]. lack of demonstrated uroselectivity in humans. One double-blind, randomized trial com- Systemic anticholinergic adverse effects (dry pared the cognitive changes in 150 healthy mouth and constipation) are common and limit male and female elderly volunteers (aged its potential. At recommended doses, it has min- >60 years) after 3-week treatments of imal impact on cognition, vision and cardiovas- darifenacin (7.5–15 mg), versus extended- cular function. In the current therapeutic release oxybutynin (10–15 mg), versus placebo model, a uroselective M3-specific receptor [42]. Results of the Name-Face Association Test antagonist would be the optimal anticholinergic showed no significant difference between drug to treat OAB. Such a drug does not yet darifenacin and placebo on delayed recall exist in the marketplace. www.future-drugs.com 729 DRUG PROFILE – Smith, Lai & Appell

The failure of current antimuscarinic drugs pathways become more prominent with aging to predictably improve symptoms of OAB with and, therefore, might contribute to OAB, par- minimum adverse effects mandates an explora- ticularly as they regulate sensation of fullness tion of other treatment paradigms. Direct and efferent transmitter release and, thus, may impairment of detrusor contractility with botu- be suitable therapeutic targets [49]. Serotonergic linum toxin A, in cases of refractory detrusor pathways via 5-HT receptors modulate the overactivity, has been reported to be effective sympathetic reflex storage function of the blad- and safe [45]. The effectiveness of botulinum der as well as inhibit the parasympathetic void- toxin may also depend upon sensory changes ing functions [50]. Opioid receptors, via decreases in purinergic and vanilloid recep- dopaminergic pathways and noradrenergic tor concentrations [46]. The incidence of overac- α-receptors may also be targets for treatment [3]. tive bladder increases with age and may be a Gabapentin has been reported to relieve symp- result of changes in urothelial receptor func- toms in some patients otherwise refractory to tion. Reports on the effects of age have demon- antimuscarinic therapy [51]. The use of local strated a decrease in M3 receptors, but the effect anesthetics or intravesical vanilloid, such as cap- on the relative concentration of M3 and M2 saicin or resiniferatoxin, to dampen afferent receptors is not agreed upon [47,48]. Purinergic activity has been a subject of research [52].

Highlights

• Darifenacin is a M3-selective receptor antagonist for the treatment of overactive bladder. • Despite encouraging animal data, it does not appear to be uroselective, and may cause systemic side effects (dry mouth and constipation). • It has been demonstrated to be safe and effective at recommended doses (7.5 and 15 mg daily). • No head-to-head, comparative studies have compared the clinical efficacy and tolerability profile of darifenacin with other currently marketed antimuscarinics. • Darifenacin has not demonstrated a conclusive therapeutic efficacy or tolerability profile above and beyond existing antimuscarinic agents. • The use of antimuscarinic agents, while the current standard for the treatment of overactive bladder, may not represent the ideal approach to this distressing problem.

Bibliography 6. Volpicelli LA, Devineni D. The clinical 12. Alabster VA. Discovery and development 1. Stewart WF, VanRooyan JB, Cundiff GW pharmacokinetics of darifenacin. Clin. of selective M3 antagonists for clinical use. et al. Prevalence and burden of overactive Pharmacokinet. 45, 325–350 (2006). Life Sci. 60, 1053–1060 (1997). bladder in the United States. World J. Urol. 7. Anagnostraras SG, Murphy CG, 13. Smith CM, Wallis RM. Characterization 20, 327–336 (2003). Hamilton SE et al. Selective cognitive of [3H]-darifenacin as a novel radioligand 2. Getsios D, El-Hadi W, Caro I et al. dysfunction in acetylcholine M1 muscarinic for the study of muscarinic M3 receptors. Pharmacological management of overactive receptor mutant mice. Nat. Neurosci. 6, J. Recept. Signal Transduct. Res. 17, bladder: a systematic and critical review of 51–58 (2003). 177–185 (1997). published economic evaluations. 8. Drachman DA, Noffsinger D, Sahakian BJ 14. Wallis RM, Burges RA, Cross PE et al. Pharmacoeconomics 23(10), 995–1006 et al. Aging, memory, and the cholinergic Darifenacin, a selective muscarinic (2005). system: a study of dichotic listening. M3 antagonist. Pharm. Res. 31(Suppl.), 54 3. Andersson, KE. Potential benefits of Neurobiol. Aging 1, 39–43 (1980). (1995). muscarinic M3 receptor selectivity. Eur. 9. Grober E, Leipzig RM, Lipton RB et al. 15. Nelson CP, Gupta P, Napier CM et al. Urol. Suppl. 1, 23–28 (2002). Does scopolamine directly impair memory? Functional selectivity of muscarinic 4. Harriss DR, Marsh KA, Birmingham AT J. Cogn. Neurosci. 1, 327 (1989). receptor antagonists for inhibition of et al. Expression of muscarinic M3-receptors 10. Gautam D, Heard TS, Cui Y et al. M3-mediated phosphoinositide responses coupled to inositol phospholipids hydrolysis Cholinergic stimulation of salivary secretion in guinea pig urinary bladder and in human detrusor cultured smooth muscle studied with M1 and M3 muscarinic submandibular salivary gland. cells. J. Urol.154, 1241–1245 (1995). receptor single- and double-knockout mice. J. Pharmacol. Exp. Ther. 310(3), 5. Somlyo AP, Walker JW, Goldman YE et al. Mol. Pharmcol. 66, 260–267 (2004). 1255–1265 (2004). Inositol triphosphate, calcium and muscle 11. Bymaster FP, Carter PA, Zhang L et al. 16. Wallis RM, Napier CM. Muscarinic contraction. Philos. Trans. R. Soc. Lond. B Investigation into the physiological role of antagonists in development for disorders Biol. Sci. 320(1199), 399–414 (1988). muscarinic M2 and muscarinic M4 and M4 of smooth muscle function. Life Sci. 64, receptor subtypes using receptor knockout 395–401 (1999). mice. Life Sci. 68, 2473–2479 (2001).

730 Therapy (2006) 3(6) Darifenacin – DRUG PROFILE

17. Yoshida M, Miyamae K, Murakami S et al. 26. Lai HH, Gross M, Boone TB, Appell RA. 37. Abrams P, Freeman R, Anderstrom C et al. Comparison of pharmacological effects of Pharmacologic and surgical management of Tolterodine, a new antimuscarinic agent, is various antimuscarinic drugs on human detrusor instability. In: Female Urology and as effective but better tolerated than isolated urinary bladder. Neurourol. Urogynecology. Vasavada SP, Appell R, oxybutynin in patients with overactive Urodyn. 20, 359 (2001). Peter KS, Raz S (Eds). Marcel Dekker, New bladder. Br. J. Urol. 81(6), 801–810 (1998). 18. Miyamae K, Yoshida M, Murakami S et al. York, USA 191–214 (2005). 38. Drutz H, Appell RA, Gleason D et al. Pharmacological effects of darifenacin on 27. Lawrence M, Guay DR, Benson SR et al. Clinical efficacy and safety or tolterodine human isolated urinary bladder. Immediate-release oxybutynin versus compared to oxybutynin and placebo in Pharmacology 64(9), 205–211 (2003). tolterodine in detrusor overactivity: a patients with overactive bladder. Int. 19. Quinn P, McIntyre P, Miner WD et al. population analysis. Pharmacology 20(4), Urogynecol. J. Pelvic Floor Dysfunct. 10(5), In vivo profile of darifenacin, a selective 470–475 (2000). 283–289 (1999). muscarinic M3 receptor antagonist 28. Kelleher CJ, Cardozo LD, Khullar V et al. A 39. Appell RA. Clinical efficacy and safety of (abstract). Br. J. Pharm. 119, 198 (1996) new questionnaire to assess the quality of life tolterodine in the treatment of overactive Joint Meeting of the British of urinary incontinent women. Br. J. Obstet. bladder: a pooled analysis. Urology Pharmacological Society, the Gynecol. 104(9), 988–993 (1997). 50(Suppl. 6A), 90–96 (1997). Pharmacological Society of Canada, and 29. Haab F, Stewart L, Dwyer P. Darifenacin, an 40. Kay GG, Wesnes KA. Pharmacodynamic the Canadian Society for Clinical M3 selective receptor antagonist, is an effects of darifenacin, a muscarinic M3 Pharmacology (1996). effective and well-tolerated once-daily selective receptor antagonist for the 20. Gupta P, Anderson C, Carter A et al. In treatment for overactive bladder. Eur Urol. treatment of overactive bladder, in healthy vivo bladder selectivity of darifenacin, a 45, 420–429 (2004). volunteers. BJU Int. 96, 1055–1062 (2005). new M3 antimuscarinic agent, in the 30. Zinner N, Susset J, Gittelman M et al. 41. Lipton RB, Kolodner K, Wesnes K. anesthetized dog. Eur. Urol. Suppl. 1, 131 Efficacy, tolerability and safety of Assessment of cognitive function of the (2002). XVIIth Congress of the European darifenacin, an M3 selective receptor elderly population: effects of darifenacin. Association of Urology, Birmingham, UK antagonist: an investigation of warning time J. Urol. 173, 493–498 (2005). (2002). in patients with OAB. Int. J. Clin. Pract. 42. Kay G, Crook T, Rekeda L et al. Differential 21. Skerjanec A. The clinical 60(1), 119–126 (2006). effects of the antimuscarinic agents pharmacokinetics of darifenacin. Clin. 31. Hill S, Khullar V, Wyndaele JJ et al. Dose darifenacin and oxybutynin ER on memory Pharmacokinet. 45, 325–350 (2006). response with darifenacin, a novel once- in older subjects. Eur. Urology 50(1), 22. Kerbusch T, Milligan PA, Karlsson MO. daily M3 selective receptor antagonist for 317–326 (2006). Assessment of the relative in vivo potency the treatment of overactive bladder: results 43. Devineni D, Skerjanec A, Woodworth TG. of the hydroxylated metabolite of of a fixed dose study. Int. Urogynecol. J. 17, Low central nervous system (CNS) darifenacin in its ability to decrease 239–247 (2006). penetration by darifenacin, a muscarinic M3 salivary flow using pooled population 32. Steers W, Corcos J, Foote J et al. An selective receptor antagonist, in rats. pharmacokinetic-pharmacodynamic data. investigation of dose titration with Summer Meeting of the British Br. J. Clin. Pharmacol. 57(2), 170–180 darifenacin, an M3-selective receptor Pharmacological Society, Cambridge, UK (2004). antagonist. BJU Int. 95, 580–586 (2005). (2005). 23. Kerbusch T, Wahlby U, Milligan PA et al. 33. Chapple C, Steers W, Norton P et al. A 44. Foote J, Glavind K, Kralidis G et al. Population pharmacokinetic modelling of pooled analysis of three Phase III studies ton Treatment of overactive bladder in the older darifenacin and its hydroxylated investigate the efficacy, tolerability and population: pooled analysis of three metabolite using pooled data, safety of darifenacin, a muscarinic M3 Phase III studies of darifenacin, an M3 incorporating saturable first-pass selective receptor antagonist, in the selective receptor antagonist. Eur. Urol. 48, metabolism, CYP2D6 genotype and treatment of overactive bladder. BJU Int. 95, 471–477 (2005). formulation-dependent bioavailability. Br. 993–1001 (2005). 45. Rajkumar GN, Small DR, Mustafa AW J. Clin. Pharmacol. 56, 639–652 (2003). 34. Cardozo L, Dixon A. Increased warning et al. A prospective study to evaluate the 24. Rosario DJ, Cutinha PE, Chapple CRF time with darifenacin: a new concept in the safety, tolerability, efficacy and durability of et al. The effects of single dose darifenacin management of urinary urgency. J. Urol. response of intravesical injection of on cystometric parameters and salivary 173, 1214–1218 (2005). botulinum toxin type A into detrusor flow in patients with urge incontinence 35. Zinner N, Tuttle J, Marks L. Efficacy and muscle in patients with refractory idiopathic secondary to detrusor instability. Eur Urol. tolerability of darifenacin, a muscarinic M3 detrusor overactivity. BJU Int. 96, 848–852 30(Suppl.), 240 (1996). XIIth Congress of selective receptor antagonist (M3 SRA), (2005). the European Association of Urology, compared with oxybutynin in the treatment 46. Apostolidis A, Popat R, Yiangou V et al. Paris, France (1996). of patients with overactive bladder. World J. Decreased sensory receptors P2X3 and 25. Rosario DJ, Leaker BR, Smith DJ et al. A Urol. 23, 248–252 (2005). TRPV1 in suburothelial nerve fibers pilot study of the effects of multiple doses 36. Haab F, Corcos, J, Siami P et al. Long-term following intradetrusor injections of of the M3 muscarinic receptor agonist treatment with darifenacin for overactive botulinum toxin for human detrusor darifenacin on ambulatory parameters of bladder: results of a 2-year, open-label overactivity. J. Urol. 174, 977–982 (2005). detrusor activity in patients with detrusor extension study. BJU Int. 47. Mansfield KJ, Lui L, Mitchelson FJ, instability. Neurourol. Urodyn. 14(5), DOI:10.1111/l.1464–410X.2006.06439.x Moore KH et al. Muscarinic receptor 464–465 (1995). (2006) (Epub ahead of print). subtypes in human bladder detrusor and mucosa, studied by radioligand binding and www.future-drugs.com 731 DRUG PROFILE – Smith, Lai & Appell

quantitative competitive RT-PCR: changes 51. Kim YT, Kwon DD, Kim J et al. H Henry Lai, MD, Senior Fellow in aging. Br. J. Pharm. 144, 1089–1099 Gabapentin for overactive bladder and Division of Voiding Dysfunction & Female Urology, (2005). nocturia after anticholinergic failure. Int. Scott Department of Urology, Baylor College of 48. Wuest M, Morgenstern K, Graf EM et al. Braz. J. Urol. 30, 275–278 (2004). Medicine, 6560 Fannin, Suite 2100 Houston, Cholinergic and purinergic responses in 52. Fowler CJ. Bladder afferents and their role TX 77030, USA isolated human detrusor in relation to age. in the overactive bladder. Urology Rodney A Appell, MD, Professor & Chief J. Urol. 173, 2182–2189 (2005). 59(Suppl. 1), 37–42 (2002). Division of Voiding Dysfunction & Female Urology, 49. Fry CH, Ikeda Y, Harvey R et al. Control of Scott Department of Urology, Baylor College of bladder function by peripheral nerves: Affiliations Medicine, 6560 Fannin, Suite 2100 Houston, avenues for novel drug targets. Urology Phillip P Smith, MD, Senior Fellow TX 77030, USA 63(Suppl. 1), 24–31 (2004). Division of Voiding Dysfunction & Female Urology, Tel.: +1 713 798 6115 50. deGroat WC. Influence of central Scott Department of Urology, Baylor College of Fax: +1 713 798 8185 serotonergic mechanisms on lower urinary Medicine, 6560 Fannin, Suite 2100 Houston, [email protected] tract function. Urology 59(Suppl. 1), 30–36 TX 77030, USA (2002).

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