Pharmacokinetics, Safety, and Tolerability of Solifenacin in Patients With Renal Insufficiency

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1 J Pharmacol Sci 103, (2007) Journal of Pharmacological Sciences 2007 The Japanese Pharmacological Society Full Paper Pharmacokinetics, Safety, and Tolerability of Solifenacin in Patients With Renal Insufficiency Ronald A. Smulders 1, *, Neila N. Smith 2, Walter J. Krauwinkel 1, and Timothy J. Hoon 2 1 Astellas Pharma Europe BV, Leiderdorp, The Netherlands 2 Astellas Pharma US, Deerfield, IL 60015, USA Received July 19, 2006; Accepted November 26, 2006 Abstract. To evaluate the pharmacokinetics, safety, and tolerability of solifenacin in patients with mild, moderate, or severe renal disease, eighteen patients with renal disease and six healthy volunteers received a single oral dose of solifenacin (10 mg). Pharmacokinetic parameters were assessed from blood samples drawn over a 360-h period. Safety and tolerability were also evaluated. Total mean ± S.D. exposure (ng h/ml) to solifenacin in healthy individuals (1190 ± 403) was increased in patients with renal disease (mild: 1784 ± 792, moderate: 1559 ± 555, severe: 2530 ± 700), and elimination half-life (mean ± S.D. [h]) was prolonged (healthy: 68.2 ± 27.2, mild: 89.1 ± 34.5, moderate: 90.6 ± 27.3, severe: 111 ± 38.3). A significant correlation was found between creatinine clearance and pharmacokinetic parameters for exposure and apparent oral clearance. No deaths or serious adverse events occurred during the study. Solifenacin 10 mg was well tolerated in patients with renal disease. Solifenacin displays a higher exposure and a prolonged half-life in patients with renal impairment, especially severe. Therefore, while no special cautions are necessary for patients with mild/moderate renal impairment, patients with severe renal impairment should receive no more than 5 mg solifenacin once daily. Keywords: overactive bladder, urgency, urge incontinence, renal insufficiency, pharmacokinetics Introduction The International Continence Society defines overactive bladder syndrome (OAB) as urgency, with or without urge incontinence, usually with frequency and nocturia (1). The symptoms suggest urodynamically demonstrable detrusor muscle overactivity and occur in the absence of local pathologic factors that might account for them. An estimated million persons worldwide have symptoms of OAB (2), while epidemiologic evidence indicates that symptoms of OAB are common and likely affect up to 22% of European adults, with prevalence increasing with age (3). Urgency is the defining symptom of OAB and is reported by 54% of patients (4). Patients with OAB, even those who remain continent, experience decrements in health-related daily functioning and quality of life (2, 4 6). Symptoms of OAB are increasingly being recognized as an issue of *Corresponding author. ronald.smulders@eu.astellas.com Published online in J-STAGE doi: /jphs.FP concern to a range of healthcare providers, including urologists, gynecologists, and primary care practitioners. Urinary bladder contraction is regulated by the parasympathetic nervous system, via stimulation of muscarinic receptors located in the detrusor muscle (7, 8). Currently, treatment of OAB is focused on controlled relaxation of the detrusor muscle through the use of muscarinic receptor antagonists (8 11). However, the most commonly used agents (e.g., oxybutynin and tolterodine) are associated with side effects such as dry mouth that may limit patient compliance and, therefore, overall efficacy (12 14). The recent Overactive Bladder: Performance of Extended Release Agents (OPERA) trial (14) reported that the extended-release formulation of oxybutynin was more effective than extended-release tolterodine in reducing micturition frequency and the proportion of patients with incontinence; however, extended-release oxybutynin was associated with a higher incidence of dry mouth than the extended-release tolterodine. Therefore, agents with more favorable efficacy to side effects ratios are needed. 67

2 68 RA Smulders et al Solifenacin succinate is a once-daily, muscarinic receptor antagonist, showing tissue preference for the bladder over the salivary gland in animal models (15, 16). Solifenacin has been shown in clinical studies to produce statistically significant improvements in all symptoms of OAB (17 20). Solifenacin has an absolute bioavailability of approximately 90% (21) and is extensively metabolized in the liver, primarily by the P450 isoenzyme 3A4. Approximately 70% of an oral dose is excreted in the urine, with approximately 11% excreted as the parent compound and approximately 60% excreted as metabolites. Evaluation of solifenacin pharmacokinetics (PK) in patients with renal impairment is important, not only because solifenacin metabolites are renally excreted, but also because renal dysfunction may affect the metabolic capacity of the liver resulting in a lower metabolic clearance of solifenacin (22, 23). In addition, solifenacin is highly bound to α 1 -acid glycoprotein (α1-agp), and plasma levels of α1-agp are generally higher in patients with renal failure (24, 25). This may result in a lower fraction of unbound solifenacin (f u ) and, consequently, a reduced clearance and volume of distribution in patients with renal impairment. Because both OAB and renal impairment affect older patients (4, 26), solifenacin would likely be administered to some patients with renal impairment. This study was designed to evaluate the PK, safety and tolerability of solifenacin following a single, oral 10-mg dose in patients with mild, moderate, or severe renal disease compared with healthy volunteers. This dose is twice the recommended starting dose of 5 mg once daily. Materials and Methods Study design This was an open-label, multi-site study that enrolled 18 patients with renal disease (6 mild, 6 moderate, and 6 severe) and 6 weight- and age-matched healthy volunteers. Renal impairment was defined according to 24-h measured creatinine clearance values. The study protocol, the protocol amendment, and the informed consent forms were reviewed and approved by an institutional review board. Study participants provided written informed consent prior to study entry. The informed consent form included a full explanation of the nature and purpose of the study. The study was conducted in accordance with the Declaration of Helsinki, the United States (US) Food and Drug Administration s Good Clinical Practice Guidelines, and Title 21 of the US Code of Federal Regulations Parts 50, 56, and 312. After an overnight fast, a single 10-mg dose of solifenacin was administered orally to all study participants on Day 1. This dose was chosen since it is the highest recommended therapeutic dose for the treatment of overactive bladder. The 10-mg dose was considered safe, even for patients with renal impairment, as it has been shown that a single dose of solifenacin up to 100 mg is well tolerated by healthy subjects (27). Compliance was assessed by mouth check. Pharmacokinetic assessments for total solifenacin were calculated for each study participant. The PK parameters assessed included the following: C max (maximum observed plasma concentration), t max (time to maximum plasma concentration), AUC 0 t (area under the plasma concentration-time curve to the last quantifiable plasma sample), AUC 0 (area under the plasma concentrationtime curve extrapolated to infinity), t 1/2 (apparent terminal phase half-life), CL/F (apparent oral clearance), and f u (fraction of unbound solifenacin [calculated as unbound solifenacin concentration divided by total solifenacin concentration at 6 and 24 h post-dose]). Blood samples were taken via an indwelling venous catheter or direct venipuncture. Serial blood samples were collected pre-dose and at 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 48, 96, 120, 168, 216, 264, 312, and 360 h post-dose. Serum α1-agp concentration and solifenacin protein binding were assayed from samples taken at screening/check-in, 6 and 12 h post-dose. Physical examination, 12-lead electrocardiogram (ECG), clinical chemistry, hematology, and urinalysis tests were performed at the screening/check-in and on Day 15. Vital signs were measured at screening/checkin, on Day 1 pre-dose and at 6 and 12 h post-dose, and on Days 2 to 5 at 7, 9, 11, 13, and 15 h post-dose. Seated blood pressure and pulse were measured after the study participant had been seated for at least 5 min. Safety was evaluated on the basis of treatment-emergent signs and symptoms, vital signs, ECGs, physical examination findings, and clinical laboratory assessments. Adverse events (AE) data were obtained by questioning the study participants at each study visit. These and all other AEs reported by the study participants were recorded. Study participants Individuals eligible for enrolment included men and women aged 18 to 80 years who met renal impairment criteria as defined by the following 24-h measured creatinine clearance categories: >80 ml/min (healthy), 50 to 80 ml/min (mild impairment), 30 to 49 ml/min (moderate impairment), and 10 to 30 ml/min (severe impairment). Patients were screened for study eligibility prior to and on the day of check-in, which occurred 2 days before study initiation. Enrollees were required to be within 40% of their ideal body weight. Only

3 Solifenacin in Renally-Impaired Patients 69 individuals with normal creatinine clearance values and normal laboratory values were permitted to enroll as age- and weight-matched controls. Enrollees had to agree to stop use of all prescription, non-prescription, and herbal supplements for 30 days prior to study initiation and throughout the study, unless specifically allowed by the investigator. In addition, enrollees had to agree to not consume grapefruit juice for 2 weeks prior to and throughout the study duration. Negative screening tests for drugs of abuse, hepatitis, and human immunodeficiency virus (HIV) were required for enrollment. Women who were pregnant, lactating, or not using a double-barrier method of contraception were excluded, in addition to women who were postmenopausal for less than 1 year. Individuals with gastrointestinal disease, multiple myeloma, chronic leukemia, hepatic disease, diabetes mellitus, or any other systemic disease (other than renal insufficiency) with the potential to confound the study results were excluded from enrollment. Additional exclusion criteria included the use of warfarin, digoxin, or antiepileptics; use of inhibitors or inducers of CYP 3A4; excessive smoking (>10 cigarettes/day or >2 cigars/day); excessive coffee consumption (>8 cups/day); presence of obstructive uropathy symptoms; and a history of drug allergies or reactions. Assay methodology Analysis for solifenacin was performed by the Bioanalysis and Drug Metabolism section of Astellas Europe BV using high performance liquid chromatography-mass spectrometry (HPLC-MS) with a lower limit of quantification of 0.5 ng/ml and an upper limit of quantification of 100 ng/ml. Solifenacin was isolated by solid phase extraction after addition of an internal standard. To determine the unbound plasma concentration of solifenacin (at a total plasma concentration of ng/ml), samples were ultrafiltrated at 1952 g for 30 min at room temperature. After addition of the internal standard to the ultrafiltrate, an aliquot was injected into the HPLC-MS system. The precision of this method varied between 6.3% and 7.4%, and the accuracy varied between 8.3% and 3.8% (28). Statistical analyses Sample size was chosen based on other studies employing a similar design, not on power calculations. For continuous variables, descriptive statistics included the number of participants reflected in the calculation, mean, standard deviation (S.D.), median, minimum, and maximum; frequencies and percentages were displayed for categorical data. Analysis included all individuals who were enrolled, had received a single dose of 10 mg solifenacin, had sufficient baseline data available, and had data available for analysis after dosing. All statistical comparisons were performed using two-sided tests at the α = 0.05 significance level unless specified otherwise. The null hypothesis was that there was not a difference in renally-impaired patients and healthy normal subjects. All summaries, analyses, and data listings were generated using SAS Version 8.2. All PK calculations, except for f u, were performed using WinNonlin Professional Edition (Version 3.3; Pharsight Corporation, Mountain View, CA, USA). Calculations for f u were performed by SAS version 8.02 (SAS Institute Inc., Cary, NC, USA). Concentrations below the limit of quantification (LOQ) were treated as zero values. The effect of renal impairment in the test groups was compared with the healthy group using analysis of variance (ANOVA). The PK variables were natural log transformed prior to analysis. The effect of renal impairment was assessed by examining the 90% confidence intervals (CI) for the ratio of the renal group mean relative to the healthy group mean. If the 90% CI based on natural log (ln)- transformed data for the renal group mean relative to the normal healthy group mean fell within 70% to 143% for C max and 80% to 125% for AUC 0 t and AUC 0, then no effect of renal impairment on PK was concluded. The Kruskal-Wallis test was used to examine t max. Linear regression analyses were performed to study the relationship between PK parameters and creatinine clearance. Safety was assessed by summarizing the number and percentage of patients or subjects with treatmentemergent AEs for each group. Laboratory safety results, vital signs, and physical examination findings were also summarized for each group at baseline and post-dose assessment at Day 15. The 12-lead ECG findings were summarized descriptively. Mean change from baseline to Day 15 was calculated and summarized by group. Results Study participant characteristics A total of 18 patients with renal impairment and six healthy subjects were enrolled in the study. All enrollees completed the study. Table 1 shows the study population stratified according to renal status category as determined by mean measured creatinine clearance values. The population was predominately Caucasian and African American, and 16 males and 8 females were enrolled. The healthy subjects were approximately ageand weight-matched with the renally-impaired patients. Overall, the study participants ranged in age from 41 to 80 years (mean: 58 years). There were no major differences in the medical histories of the renally-impaired

4 70 RA Smulders et al Table 1. Demographic characteristics of study participants Renal status Demographic Healthy Mild Moderate Severe Number of patients Age (y) (range) Weight (kg) (range) Height (cm) (range) Creatinine clearance (ml/min) (range) 54.0 ± 6.1 ( ) 89.5 ± ( ) ± ( ) ± 7.2 ( ) 64.0 ± 10.3 ( ) 77.1 ± 8.54 ( ) ± ( ) 63.0 ± 9.8 ( ) 53.0 ± 6.6 ( ) 90.5 ± ( ) ± 6.50 ( ) 40.0 ± 6.3 ( ) 62.0 ± 12.5 ( ) 87.4 ± ( ) ± 5.56 ( ) 19.0 ± 4.6 ( ) α1-agp at check-in (mg/dl) 88 ± ± ± ± 25 6 h post-dose (mg/dl) 91 ± ± ± ± h post-dose (mg/dl) 94 ± ± 8 90± ± 39 Sex Male Female Race Caucasian African-American Mid-Eastern Data are each a mean ± S.D. α1-agp = alpha-1-acid glycoprotein. Fig. 1. Mean plasma concentration-time profile for total solifenacin in renally-impaired patients and healthy subjects (normal scale). patients and healthy subjects, aside from renal status. Approximately one third of the renally-impaired group was taking concomitant medications for hypertension and diabetes. There were no study discontinuations. Pharmacokinetic parameters As illustrated by the mean plasma-concentration-time data displayed in Fig. 1, there is a higher exposure for total solifenacin in renally-impaired patients compared with healthy subjects. Table 2 summarizes the PK parameters for the healthy and the renally-impaired groups. Relative to the healthy group, in the renallyimpaired groups, AUC 0 and t 1/2 was generally higher (total mean ± S.D. AUC 0 [ng h/ml]: healthy: 1190 ± 403, mild renal disease: 1784 ± 792, moderate renal disease: 1559 ± 555, severe renal disease: 2530 ± 700; t 1/2 mean ± S.D. [h]: healthy: 68.2 ± 27.2, mild renal disease: 89.1 ± 34.5, moderate renal disease:

5 Solifenacin in Renally-Impaired Patients 71 Table 2. Summary of pharmacokinetic parameters for total plasma solifenacin Pharmacokinetic parameters Renal status C max (ng/ ml) t max a (h) AUC 0 t (ng h/ml) AUC 0 (ng h/ml) t 1/2 (h) CL/F (L/h) Healthy 15.7 ± (5.00, 8.00) Mild 17.5 ± (3.00, 8.02) Moderate 15.2 ± (3.00, 6.00) Severe 20.6 ± (2.00, 8.00) 1118 ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± 0.95 Data are each a mean ± S.D. except for t max. a Median (min, max) shown for t max. n = six subjects in each group. C max = maximum observed plasma concentration, t max = time to maximum plasma concentration, AUC 0 t = area under the plasma-concentration-time curve to the last quantifiable plasma sample, AUC 0 = area under the plasma-concentration-time curve extrapolated to infinity, t 1/2 = apparent terminal phase half-life, CL/ F = apparent oral clearance. Table 3. Comparison of pharmacokinetic parameters for total solifenacin by renal status Parameter Healthy mean a Mild renal mean a Mild renal/healthy ratio b (90% CI) c Moderate renal mean a Moderate renal/healthy ratio b (90% CI) c Severe renal mean a Severe renal/healthy ratio b (90% CI) c ln(c max) (83.5, 152.0)* ln(auc 0 t) (96.2, 203.0)* ln(auc 0 ) (98.3, 211.0)* ln(cl/f) (47.3, 102.0) ln(t 1/2) (86.3, 188.0) (71.7, 131.0) (84.9, 179)* (87.4, 188.0)* (53.2, 114) (91.2, 198.0) (91.3, 166.0)* (135.0, 285.0)* (147.0, 316.0)* (31.7, 68.1) (110.0, 239.0) a Least squares mean from ANOVA. Natural log parameter means calculated by transforming the natural log means back to the linear scale. b Ratio of parameter means for natural log transformed parameters (expressed as a percent). Natural log transformed ratios transformed back to linear scale. c 90% CI for ratio of parameter means of natural log transformed parameters (expressed as a percent). Natural log transformed confidence limits transformed back to linear scale. *90% CI fell outside the pre-specified range of 70% to 143% (C max) or 80% to 125% (AUC 0 t, AUC 0 ). CI = confidence interval, ln = natural log, C max = maximum observed plasma concentration, AUC 0 t = area under the plasma-concentration-time curve to the last quantifiable plasma sample, AUC 0 = area under the plasma-concentration-time curve extrapolated to infinity, CL/F = apparent oral clearance, t 1/2 = apparent terminal phase half-life ± 27.3, severe renal disease: 111 ± 38.3). In addition, CL/F showed a decreasing trend. Only a marginal effect on C max was observed. The median time to t max values (range: 3.00 to 8.02 h) were comparable between all patients, except for those with severe renal disease in whom t max was approximately half that of other patients. Comparisons of the mean PK parameter values for renally-impaired groups versus healthy subjects are summarized in Table 3. Analyses revealed a significant effect of renal impairment on the PK of total solifenacin. However, the 90% CI for the natural log (ln) of C max for the comparison between the moderate impairment and healthy groups was within the (70, 143) range. For all comparisons, the 90% CI for ln(auc 0 t ) and ln(auc 0 ) were outside the (80, 125) range, with mean values for the severe impairment group being approximately two times higher than those for the healthy group. Extensive plasma protein binding for solifenacin was observed in all groups. Compared with the other groups, higher serum levels of α1-agp were found in patients with severe renal impairment (Table 1). In the groups of healthy subjects and patients with mild or moderate renal impairment, similar α1-agp serum levels were found. Within the different cohorts, there appeared to be no differences in serum α1-agp between the screening, 6-, and 24-h values.

6 72 RA Smulders et al Fig. 2. Total solifenacin C max versus creatinine clearance for all study participants. C max = maximum observed plasma concentration and CrCl = creatinine clearance. Fig. 3. Total solifenacin AUC 0 versus creatinine clearance for all study participants. AUC 0 = area under the plasma concentrationtime curve extrapolated to infinity and CrCl = creatinine clearance. Table 4. Relationship between creatinine clearance and C max, AUC 0 t, AUC 0, and CL/F of solifenacin, and statistical analysis results Parameter Intercept estimate 95% confidence interval Slope estimate (P-value) 95% confidence interval C max (0.4384) to AUC 0 t (0.0082) to 2.99 AUC (0.0034) to 4.94 CL/F (0.0173) to C max = maximum observed plasma concentration, AUC 0 t = area under the plasma-concentration-time curve to the last quantifiable plasma sample, AUC 0 = area under the plasma-concentration-time curve extrapolated to infinity, CL/F = apparent oral clearance. Unbound solifenacin plasma concentrations at 6- and 24-h post-dose were very low or below the LOQ in approximately 50% of the study participants. In those subjects in which f u could be determined, its value was lower than 4%. However, the number of participants in which f u could be determined (14/24) was too small to evaluate the possible effect of renal impairment. Linear regression analysis showed no statistically significant relationship (95% CI for slope [ 0.112, ]) for creatinine clearance and C max, as illustrated in Fig. 2 and Table 4. However, significant relationships with creatinine clearance were observed for AUC 0 t, AUC 0, and CL/F. Both AUC 0 (Fig. 3) and AUC 0 t showed a decreasing trend while CL/F showed an increasing trend with higher values of creatinine clearance. Since values of PK parameters based on unbound plasma concentrations of solifenacin could only be assessed in 8 subjects, a useful regression analysis between creatinine clearance and the unbound PK parameters could not be performed. Safety and tolerability The AEs that were expected with the use of antimuscarinics such as solifenacin included dry mouth, constipation, and blurred vision. No deaths or serious AEs occurred during the study. Twenty-six AEs were reported, of which the majority (21/26) were determined to be unrelated to the study drug. Of the 26 AEs, 16 were considered mild, nine were considered moderate, and one was considered severe (muscle cramps). The incidence of AEs appeared to be unrelated to kidney function. The two AEs that were considered probably related to the study drug included dry mouth in one healthy subject and dry mouth in one patient with moderate renal impairment. Three AEs in severe renal impairment patients were considered possibly related and included pitting oedema and muscle cramps. Minor fluctuations occurred in laboratory findings that were generally consistent with the disease state or pre-existing illness (e.g., diabetes) of some patients. There were no clinically relevant changes in vital signs, ECG parameters, or physical examinations. Discussion Overactive bladder is highly prevalent and becomes more common with advancing age (3, 29 31). Pharmacologic treatment targeting the detrusor muscle with antimuscarinic agents is currently the standard of care; however, the most commonly used agents are associated

7 Solifenacin in Renally-Impaired Patients 73 with anticholinergic side effects that may reduce patient compliance and tolerability (32). Millions of affected individuals in Europe and the US could benefit from the development of new agents with improved tolerability profiles and flexible dosing options (32). Solifenacin is an oral, once-daily agent that has been shown to significantly reduce all symptoms of OAB, including urgency, urinary frequency, and incontinence, compared with placebo in symptomatic patients (17 20). This study was undertaken to assess the PK and safety of solifenacin in patients with mild, moderate, or severe renal impairment. Results showed that a single oral dose of solifenacin at 10 mg in healthy subjects and renally-impaired patients was associated with few AEs and was well tolerated. There were no clinically relevant, treatment-emergent changes in physical examination, ECG, or laboratory findings. Analyses of the PK parameters revealed that total exposure to solifenacin was generally increased and elimination half-life was prolonged in the renally impaired patients, as compared with healthy subjects. However, the effect of renal impairment status on C max was marginal. Linear regression analysis examining the relationship between creatinine clearance and PK parameters showed no significant relationship for C max, but a statistically significant relationship was found for total exposure and oral clearance. The higher AUC and consequently lower CL/F observed in renally-impaired patients correlated with a decrease in creatinine clearance. Since the role of renal excretion in the elimination of solifenacin is relatively minor (approximately 11%), the lower solifenacin clearance in renally impaired patients is not necessarily directly related to the reduced capacity of the kidneys to excrete solifenacin. It may, however, reflect the reduced metabolic capacity of the liver that is sometimes a consequence of renal impairment. Furthermore, solifenacin is highly bound to α1-agp, the concentration of which was increased in the group of patients with severe renal impairment. A change in α1-agp may, therefore, have affected the unbound fraction of solifenacin and, consequently, its clearance. However, this possibility could not be tested due to the limited number of subjects in which the unbound fraction could be assessed. One limitation of this study is that only a single dose that is twice the recommended starting dose was used to evaluate the effects on PK and safety in renal impairment. As such, this study does not address chronic administration of solifenacin in the clinical setting. In this study, however, the total exposure to solifenacin was two times higher in patients with severe renal impairment than in healthy volunteers. A single dose of 10 mg resulted in AUC 0 of 1190 ng h/ml in healthy subjects and 2530 ng h/ml in subjects with severe renal impairment, an approximate 2-fold difference. Given the linear PK of solifenacin (27), a 5-mg dose in severely impaired subjects is expected to result in an AUC 0 of approximately 1250 ng h/ml. The PK characteristics of solifenacin do not change during multiple dosing. Therefore, in steady-state, which is expected to be reached after 10 days in healthy subjects and after 17 days in patients with severe renal impairment, AUC 0 24h of solifenacin would amount to 1190 ng h/ml in healthy subjects at a dose of 10 mg once daily and to 1250 ng h/ml at a dose of 5 mg once daily in subjects with severe renal impairment. These AUC 0 24h values correspond to average steady state concentrations of 50 and 52 ng/ml in healthy subjects and severely impaired subjects, respectively. Consequently, doses of solifenacin greater than 5 mg are not recommended in subjects with severe renal impairment. In conclusion, a single oral dose of solifenacin at 10 mg was well tolerated in patients with mild, moderate, and severe renal impairment. Solifenacin displays a higher exposure and a prolonged t 1/2 in patients with renal impairment relative to healthy controls; doses of solifenacin greater than 5 mg are not recommended in subjects with severe renal impairment. Acknowledgements This study was funded and sponsored by Astellas Pharma, Inc., Tokyo, Japan, including editorial support and statistical analysis. Editorial assistance was provided by Priya Venkatesan, Medicus International (New York, NY, USA). References 1 Abrams P, Cardozo L, Fall M, Griffiths D, Rosier P, Ulmsten U, et al. The standardisation of terminology in lower urinary tract function: report from the standardisation sub-committee of the International Continence Society. Urology. 2003;61: Abrams P, Wein A. Introduction: Overactive bladder and its treatments. Urology. 2000;55: Milsom I, Stewart W, Thuroff J. The prevelance of overactive bladder. Am J Man Care. 2001;6:S565 S Milsom I, Abrams P, Cardozo L, Roberts RG, Thuroff J, Wein AJ. How widespread are the symptoms of an overactive bladder and how are they managed? A population-based prevalence study. BJU Int. 2001;87: Jackson S. The patient with an overactive bladder symptoms and quality-of-life issues. Urology. 1997;50(6A Suppl): Stewart W, Herzog R. The prevelance and impact of overactive bladder in the U.S: results from the NOBLE program. Neurourol Urodynam. 2001;20: Andersson KE, Yoshida M. Antimuscarinics and the overactive detrusor which is the main mechanism of action? Eur Urol.

8 74 RA Smulders et al 2003;43: Chapple CR, Yamanishi T, Chess-Williams R. Muscarinic receptor subtypes and management of the overactive bladder. Urology. 2002;60(5 Suppl 1): Wein AJ, Rovner ES. The overactive bladder: an overview for primary care health providers. Int J Fertil Womens Med. 1999;44: Chess-Williams R. Muscarinic receptors of the urinary bladder: detrusor, urothelial and prejunctional. Auton Autacoid Pharmacol. 2002;22: Uchida M, Koganei M, Murata N, Yamaji T. Effects of 4- ethylamino-2-butynyl(2-cyclohexyl-2-phenyl)glycolate hydrochloride, a metabolite of oxybutynin, on bladder specimens and rhythmic bladder contraction in rats in comparison with oxybutynin. J Pharmacol Sci. 2004;94: Appell RA. The newer antimuscarinic drugs: bladder control with less dry mouth. Cleve Clin J Med. 2002;69:761, , Appell RA. Clinical efficacy and safety of tolterodine in the treatment of overactive bladder: a pooled analysis. Urology. 1997;50(6A Suppl): Diokno AC, Appell RA, Sand PK, Dmochowski RR, Gburek BM, Klimberg IW, et al. Prospective, randomized, double-blind study of the efficacy and tolerability of the extended-release formulations of oxybutynin and tolterodine for overactive bladder: results of the OPERA trial. Mayo Clin Proc. 2003;78: Ikeda K, Kobayashi S, Suzuki M, Miyata K, Takeuchi M, Yamada T, et al. M(3) receptor antagonism by the novel antimuscarinic agent solifenacin in the urinary bladder and salivary gland. Naunyn Schmiedebergs Arch Pharmacol. 2002;366: Ohtake A, Ukai M, Hatanaka T, Kobayashi S, Ikeda K, Sato S, et al. In vitro and in vivo tissue selectivity profile of solifenacin succinate (YM905) for urinary bladder over salivary gland in rats. Eur J Pharmacol. 2004;492: Chapple CR, Rechberger T, Al-Shukri S, Meffan P, Everaert K, Huang M, et al. Randomized, double-blind placebo- and tolterodine-controlled trial of the once-daily antimuscarinic agent solifenacin in patients with symptomatic overactive bladder. BJU Int. 2004;93: Cardozo L, Lisec M, Milard R, van Vierssen TO, Kuzmin I, Drogendijk TE, et al. Randomized, double-blind placebocontrolled trial of once-daily antimuscarinic agent solifenacin succinate in patients with overactive bladder. J Urol. 2004;172: Gittelman M, Chu FM, Klimberg I, Fincher R, Smith N, Tempel D, et al. Two randomized, double-blind, placebo-controlled, parallel-group, fixed dose, multicenter studies assess the efficacy and safety of daily oral adminstration of 10 mg YM905 versus placebo in male and female subjects with overactive bladder. AUA Western Congress, 2003; Las Vegas, USA: Abstract DP Gittelman M. The efficacy and safety of solifenacin in adults with overactive bladder: a multicenter, placebo-controlled study. Int J Gynecol Obstet. 2003;83(Suppl 3):94 (Abstract TP76). 21 Kuipers ME, Krauwinkel WJJ, Mulder H, Vissner N. Solifenacin demonstrates high absolute bioavailability in healthy men. Drugs RD. 2004;5: Dreisbach AW, Lertora JJ. The effect of chronic renal failure on hepatic drug metabolism and drug disposition. Semin Dial. 2003;16: Sun H, Frassetto L, Benet LZ. Effects of renal failure on drug transport and metabolism. Pharmacol Ther. 2006;109: Pacifici GM, Viani A, Taddeucci-Brunelli G, Rizzo G, Carrai M, Schulz HU. Effects of development, aging, and renal and hepatic insufficiency as well as hemodialysis on the plasma concentrations of albumin and alpha 1-acid glycoprotein: implications for binding of drugs. Ther Drug Monit. 1986;8: Vasson MP, Baguet JC, Arveiller MR, Bargnoux PJ, Giroud JP, Raichvarg D. Serum and urinary alpha-1 acid glycoprotein in chronic renal failure. Nephron. 1993;65: Jones CA, McQuillan GM, Kusek JW, Eberhardt MS, Herman WH, Coresh J, et al. Serum creatinine levels in the US population: third National Health and Nutrition Examination Survey. Am J Kidney Dis. 1998;32: Smulders RA, Krauwinkel WJ, Swart PJ, Huang M. Pharmacokinetics and safety of solifenacin succinate in healthy young men. J Clin Pharmacol. 2004;44: Smulders RA, Kuipers ME, Krauwinkel WJ. Multiple doses of the antimuscarinic agent solifenacin do not affect the pharmacodynamics or pharmacokinetics of warfarin or the steady-state pharmacokinetics of digoxin in healthy subjects. Br J Clin Pharmacol. 2006;62: Rovner E, Wein A. The treatment of overactive bladder in the geriatric patient. Clinical Geriatrics. 2002;10: Wein A. Definition and epidemiology of overactive bladder. Urology. 2002;60(Suppl 5A): Wagner TH, Hu TW. Economic costs of urinary incontinence in Urology. 1998;51: Wein AJ. Pharmacological agents for the treatment of urinary incontinence due to overactive bladder. Expert Opin Investig Drugs. 2001;10:65 83.