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Keywords:

  • Adult;
  • female;
  • fesoterodine;
  • gastroin-testinal transit;
  • randomized controlled trial;
  • solifenacin

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Subjects
  6. Results
  7. Discussion
  8. Acknowledgments
  9. Funding
  10. Disclosures
  11. Author contributions
  12. References

Background  The gastrointestinal effects of antimuscarinic drugs used to treat overactive bladder may be related to the selectivity of these agents for M3-muscarinic receptor subtypes. We compared the effects of non-selective (fesoterodine) and M3-selective (solifenacin) antimuscarinics on gastrointestinal transit in healthy women.

Methods  Gastric emptying (GE), small-intestinal transit (colonic filling at 6 h), colonic transit [geometric center at 24 h (GC24; primary endpoint) and 48 h (GC48)], and bowel habits were assessed by scintigraphy and bowel diaries before and after randomization to fesoterodine 8 mg, solifenacin 10 mg, or placebo (2 : 2 : 1) for 14 days. An interim analysis to finalize sample size was conducted.

Key Results  After 60 subjects [placebo (n = 12), fesoterodine (n = 25), solifenacin (n = 23)] completed the study, the study was terminated due to a prespecified criterion (sample size ≥452.5 needed to provide ≥80% power to demonstrate superiority of fesoterodine over solifenacin in GC24). Compared with baseline, (i) placebo delayed small-intestinal, but not colonic, transit, (ii) fesoterodine significantly increased GE t1/2vs placebo (17.0 min; P = 0.027), and (iii) fesoterodine and solifenacin delayed small-intestinal (−36.8% and −21.8%, respectively, < 0.001 vs placebo) and colonic transit (GC24: −0.44 and −0.49, respectively, < 0.05 vs placebo; GC48: −0.25 and −0.65, respectively, > 0.05 vs placebo). Solifenacin increased stool hardness from baseline (P = 0.010 for difference vs fesoterodine); stool frequency was comparable.

Conclusions & Inferences  In healthy women, fesoterodine had greater effects on small-intestinal transit and solifenacin had greater effects on colonic transit; the latter finding may explain why solifenacin, but not fesoterodine, increased stool hardness. (ClinicalTrials.gov ID: NCT00892034).


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Subjects
  6. Results
  7. Discussion
  8. Acknowledgments
  9. Funding
  10. Disclosures
  11. Author contributions
  12. References

Randomized controlled trials suggest that antimuscarinic drugs, the first-line treatment for overactive bladder (OAB), reduce the incidence of symptoms,1 including urgency urinary incontinence, and improve the health-related quality of life of subjects with OAB.2 Of the five known muscarinic receptors (M1–M5), M2 and M3 subtypes predominate in an approximate ratio of 3–4 : 1 in the detrusor muscle and gastrointestinal tract; however, M3 receptors predominantly mediate bladder and bowel contractility.3–5 By blocking M3-muscarinic receptors in the detrusor muscle, antimuscarinic agents reduce detrusor overactivity, increase bladder capacity, and reduce urinary urgency in OAB.

Constipation is a dose-dependent and bothersome adverse event (AE) associated with many antimuscarinic agents. A meta-analysis of randomized placebo-controlled trials of antimuscarinic agents for the treatment of OAB found that the risk of constipation may be lower with drugs that are non-selective for muscarinic receptor subtypes, such as tolterodine (odds ratio [OR] = 1.36, 95% confidence interval [CI]: 1.01–1.85) or fesoterodine (OR = 2.07, 95% CI: 1.28–3.35) than with drugs that are selective for M2- and/or M3-receptor subtypes, such as trospium (OR = 2.93, 95% CI: 2.00–4.28) and solifenacin (OR = 3.02, 95% CI: 2.37–3.84).6 This meta-analysis combined results for different doses of the antimuscarinic agents, although the incidence of constipation with some is dose-dependent. Regardless, these and other observations suggest that higher selectivity for M3-receptor subtypes and, possibly, tissue selectivity with respect to drug diffusion and active transport (e.g., bladder vs gastrointestinal tract) may explain differences in the incidence of constipation among antimuscarinic agents.7–9

Previous studies showed that tolterodine did not affect gastrointestinal or colonic transit vs placebo in healthy adults,10 whereas the M3-selective antagonist darifenacin significantly delayed small-intestinal and colonic transit compared with placebo and tolterodine.11 These studies demonstrated that darifenacin had dose-dependent effects on small intestinal and colonic transit, but only used one (i.e., lower) dose (4 mg) of tolterodine LA. Moreover, tolterodine and its metabolite 5-hydroxymethyl tolterodine (5-HMT) are equipotent active moieties that are non-selective antimuscarinic agents.12 The non-selective antimuscarinic fesoterodine is an esterified prodrug that is rapidly hydrolyzed by non-specific and ubiquitous esterases to its only active metabolite, 5-HMT,13 resulting in delivery of 5-HMT with less variability and up to 40% higher bioavailability than occurs with tolterodine extended release (ER) 4 mg.14 Hence, it is conceivable that the effects of fesoterodine on gastrointestinal transit differ from those of tolterodine, providing the rationale for this study. We compared the effects on gastrointestinal transit of the non-selective antimuscarinic fesoterodine with those of solifenacin, which demonstrates some selectivity for the M3- vs the M2-muscarinic receptor subtype.8 Because the prevalence rates of constipation15 and OAB symptoms16 are generally higher in women than in men, we evaluated gastrointestinal transit in women.

Materials and Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Subjects
  6. Results
  7. Discussion
  8. Acknowledgments
  9. Funding
  10. Disclosures
  11. Author contributions
  12. References

Study design

This was a randomized, double-blind, placebo-controlled, parallel-group, multiple-dose, clinical trial to investigate the effects of fesoterodine 8 mg and solifenacin 10 mg on gastrointestinal transit in healthy women (ClinicalTrials.gov ID: NCT00892034). The study was conducted at the Mayo Clinic, Rochester, Minnesota, from May 7, 2009, to December 4, 2009, and performed in accordance with Good Clinical Practice guidelines and the Declaration of Helsinki. The study protocol was approved by the institutional review board of the Mayo Clinic on March 30, 2009. Written informed consent was obtained from each subject before the initiation of any study procedure. The study included a 2-day baseline evaluation period and a 14-day treatment period, with seven planned study visits (Fig. 1). The screening visit at the clinic was conducted within 28 days before subject randomization and the administration of study medication to confirm eligibility criteria for enrollment, obtain written informed consent, record demographic and medical information, and conduct a full physical examination, blood pressure and heart rate measurements, a 12-lead electrocardiogram, and blood and urine safety laboratory tests after an 8-h fast. Outpatient visits took place on days −2, −1, 0 (day of randomization), 12, 13, and 14.

image

Figure 1.  Study design.

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Following an 8-h fast, subjects were randomized 2 : 2 : 1 to receive one fesoterodine 8-mg tablet, one solifenacin 10-mg capsule, or one placebo tablet/capsule, respectively, at approximately 07:00 hours (±2 h) from day 1 to day 11. The same study medication was administered after an 8-h fast on study days 12–14 by site personnel. For both drugs, the dose is the highest dose approved for clinical use.

Subjects

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Subjects
  6. Results
  7. Discussion
  8. Acknowledgments
  9. Funding
  10. Disclosures
  11. Author contributions
  12. References

Key inclusion criteria for study enrollment included healthy women aged 18–55 years (inclusive), body-mass index of 17.5–30.5 kg m−2, and a total body weight >50 kg (110 lb). Eligible subjects had no clinically relevant abnormalities identified by a detailed medical history; full physical examination, including blood pressure and heart rate measurements; a 12-lead electrocardiogram; and clinical laboratory tests. Women of childbearing potential who were currently taking oral contraceptives were eligible provided they had a negative pregnancy test prior to enrollment. Exclusion criteria included significant functional gastrointestinal disorders as assessed by an abridged Bowel Disease Questionnaire,17 anxiety or depression as assessed using the Hospital Anxiety and Depression Questionnaire,18 or clinically significant hematologic, renal, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurologic, urologic, or allergic disease; history of gastrointestinal surgeries, except appendectomy or abdominal wall hernia repair, cholecystectomy, or hysterectomy performed more than 3 months before study participation; history of febrile illness within 5 days prior to the first dose of study medication; positive urine drug screen; history of regular alcohol consumption within 6 months of screening; use of tobacco- or nicotine-containing products in excess of the equivalent of five cigarettes per day; consumption of >5 caffeinated beverages per day; 12-lead electrocardiogram demonstrating QTc >470 ms at screening; use of medications that might affect gastrointestinal transit, potent inhibitors of cytochrome P450 3A4, antifungal agents, cimetidine, monoamine oxidase inhibitors, protease inhibitors, or drugs and/or herbal preparations capable of inducing hepatic enzyme metabolism; consumption of grapefruit or grapefruit-containing products within 7 days before the first dose of study medication; blood donation of approximately one pint (500 mL) within 56 days before dosing; hypersensitivity to any components of study medication, peanut, or soya; or any laboratory abnormality that could increase the risk of study participation or could interfere with the interpretation of study results.

Assessments

Gastric emptying, small-intestinal transit, and colonic transit were assessed by established validated scintigraphic techniques19 beginning on day -2 (baseline) and on day 12 of treatment. Subjects returned to the clinic (or imaging facility) in a fasted state. Gastric emptying and small-intestinal transit were assessed using a 99mTc-labeled egg meal, and colonic transit was assessed using 111In-labeled charcoal pellets (0.10 mCi 111InCl3 mixed with a slurry of 5 mg activated charcoal) placed in a methacrylate-coated gelatine capsule. Gastric emptying was summarized as the proportion of stomach contents emptied at 2 and 4 h and by the half-time (t1/2) for gastric emptying. Colonic filling (i.e., the proportion of 99mTc reaching the colon) at 6 h was used to measure orocecal transit (i.e., a surrogate for small-bowel transit). Colonic filling was expressed by measuring the proportion of total 99mTc counts at 6 h, corrected for decay and tissue attenuation, which are in the colon, typically in the cecum and ascending colon. Overall colonic transit was summarized as the colonic geometric center (GC) at 4, 24, and 48 h. The GC represents the average of counts in different colonic regions (ascending, transverse, descending, and rectosigmoid colon) and stool, weighted by factors of 1–5, respectively, at these time points. Therefore, a higher GC represents faster colonic transit. GC48 minus GC24 values also were calculated. Ascending colonic emptying was summarized by the t1/2 calculated by linear interpolation of values on the ascending colonic emptying curve.

Each subject was asked to record each bowel movement in a bowel diary during the baseline and treatment period (from day −2 to day 14). The diary also was used to record stool consistency on the validated Bristol Stool Form Scale,20 with a score ranging from 1 = hard lumps to 7 = watery; the ease of defecation, with a score ranging from 1 = manual disimpaction to 7 = incontinent; and the proportion of bowel movements per day with satisfaction (i.e., you felt like you completely emptied your bowels). Bowel-diary data were summarized using a 3-day baseline and the last 3 days of treatment.

The investigator recorded all observed or reported AEs, the severity (mild, moderate, severe) of each AE, and the investigator’s opinion of the relationship of each AE to study medication. Blood pressure, heart rate, and laboratory test measurements were conducted at screening, day −2, and day 14 of the study.

Sample size and interim analysis

The original target sample size was 130 subjects for the intention-to-treat population (i.e., all randomized subjects). In a previous study comparing the effects of tolterodine and darifenacin on gastrointestinal transit using similar techniques, the mean values for GC24 were 2.8 (placebo), 2.7 (tolterodine ER 4 mg), 2.4 (darifenacin ER 7.5 mg), and 1.9 (darifenacin ER 15 mg).10,11 The sample size estimate was guided by assuming a mean treatment difference in GC24 between fesoterodine 8 mg and solifenacin 10 mg of 0.5 units (i.e., similar to the difference between darifenacin ER 15 mg and tolterodine ER 4 mg) with a common standard deviation (SD) of 0.9 units for both groups; it was estimated that a sample size of 52 subjects in each treatment group was required to provide at least 80% power (two-sided t-test, significance level α = 0.05) to detect a statistically significant difference between fesoterodine 8 mg and solifenacin 10 mg. In addition, assuming a mean treatment difference between solifenacin 10 mg and placebo of 0.7 units on GC24 with a common SD of 0.9 units for both groups, it was estimated that a sample size of 52 subjects in the solifenacin group and 26 subjects in the placebo group would provide at least 89% power (two-sided t-test, significance level α = 0.05) to detect a statistically significant difference between placebo and solifenacin 10 mg. However, the actual sample size depended on the results of an interim analysis, with a range from 60 to 200 subjects (including those who terminated early). The objective of the interim analysis was to adjust the total sample size based on the effect size on GC24; the effect size was estimated by the adjusted mean treatment difference between fesoterodine 8 mg and solifenacin 10 mg divided by the root mean square error obtained from an analysis of covariance (ancova) model using the data collected at the time the interim analysis was conducted. This analysis, which was performed under the unblinded condition when 60 randomized subjects completed the study, used the same ancova model as the final analysis. The intention-to-treat population was used for this sample size re-estimation. The decision rule was as follows: if the re-estimated total sample size (placebo + fesoterodine 8 mg + solifenacin 10 mg) based on the interim analysis results is ≤60, the study will be stopped due to overwhelming efficacy; if the re-estimated total sample size is >60, but ≤200, the study will be continued with the re-estimated total sample size within the range of 61 to 200 subjects needed to keep 80% power; if the re-estimated total sample size is >200, but <452.5 (181 subjects for fesoterodine and solifenacin group, respectively), the study will be continued with the maximum total sample size of 200 subjects; if the re-estimated total sample size is ≥452.5, the study will be stopped due to futility. There was no influence of type I error in the interim analysis, as confirmed by the theoretical calculation proposed by Shun and colleagues21 and simulation experiments.

Randomization and blinding

The investigator assigned subject numbers sequentially to the subjects as they were screened for the study. Randomization numbers were then assigned using interactive web response services to the subjects who met the inclusion criteria at day 0. Each subject received the study treatment assigned to the corresponding randomization number. Stratified randomization by age, body-mass index, and baseline GC24 value was used. In accordance with the standard operating procedures of the Mayo Clinic and Pfizer, the randomization schedule was generated by the Global Clinical Data Service department at Pfizer and kept in the custody of that department until the key break. The individuals responsible for randomization kept the container number table until the key break. In addition, when the interim analysis was conducted in a clinical research organization (independent of the sponsor), the individuals responsible for randomization sent the randomization schedule directly to the clinical research organization. Thus, blinding for all personnel and investigators of the Mayo Clinic was maintained during the double-blind phase. At the initiation of the study, the study site was instructed on the method for breaking the blind. Blinding was only to be broken in emergency situations for reasons of subject safety.

Statistical analysis

All scintigraphy and bowel-diary endpoints were analyzed using an ancova model, with treatment group as a fixed effect and baseline value, age, and body-mass index as covariates. The least-squares (LS) mean with 95% CIs, the LS mean change from baseline with 95% CIs, and the difference between treatment group LS means with 95% CIs with a significance level of α = 0.05 were calculated based on the ancova model. There were two a priori comparisons [i.e., between fesoterodine and solifenacin (primary) and between placebo and solifenacin (secondary)]. In this article, a statistically significant difference was concluded if the P value was <0.05 without controlling for multiplicity. The association between the Bristol Stool Scale score for stool consistency and colonic transit was assessed by calculating Spearman correlation coefficients. Adverse events and blood pressure, heart rate, and laboratory test measurements were summarized descriptively.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Subjects
  6. Results
  7. Discussion
  8. Acknowledgments
  9. Funding
  10. Disclosures
  11. Author contributions
  12. References

Subjects

After the interim analysis, the re-estimated total sample size was ≥452.5 to provide at least 80% power to demonstrate superiority of fesoterodine 8 mg over solifenacin 10 mg for GC24; hence, the study was terminated due to the prespecified criteria for futility. Thus, the final sample size was 60 subjects in the intention-to-treat population (placebo: 12 subjects, fesoterodine 8 mg: 25 subjects, solifenacin 10 mg: 23 subjects). The disposition of enrolled subjects is shown in Fig. 2. The characteristics of the 60 subjects at baseline were comparable for the three treatment groups (Table 1).

image

Figure 2.  Subject disposition. FESO = fesoterodine; SOLI = solifenacin.

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Table 1.   Subject characteristics at baseline (intention-to-treat population)
CharacteristicPlacebo (n = 12)Fesoterodine 8 mg (n = 25)Solifenacin 10 mg (n = 23)
  1. BMI = body-mass index.

Mean (SD) age, y33.1 (12.0)36.1 (9.9)34.5 (9.5)
Range19–5120–5518–51
Self-assigned ethnicity, n (%)
 White11 (91.7)23 (92.0)21 (91.3)
 Black1 (8.3)01 (4.3)
 Other02 (8.0)1 (4.3)
Mean (SD) body weight, kg65.1 (8.3)68.7 (9.2)66.8 (7.6)
Range54.3–79.555.0–89.850.9–82.5
Mean (SD) BMI, kg·m−224.4 (3.6)24.8 (2.6)24.3 (2.9)
Range18.8–29.820.0–30.018.7–30.3

Gastrointestinal transit

The LS mean change from baseline to treatment in the t1/2 of gastric emptying was −3.9 min for the placebo group, 17.0 min for the fesoterodine group, and 4.3 min for the solifenacin group (Table 2). The comparison between the LS mean change from baseline for the fesoterodine group and the solifenacin group was not significant (= 0.094). Compared with placebo, fesoterodine (= 0.027), but not solifenacin (= 0.368), significantly increased the mean gastric emptying t1/2 from baseline to treatment. At baseline, the percentage of colonic filling at 6 h, a measure of small-intestinal transit, was lower (i.e., slower transit) for the fesoterodine group (39.9%) and the solifenacin group (46.3%) than for the placebo group (59.8%; Table 2). After treatment, fesoterodine delayed small-intestinal transit significantly more than solifenacin (= 0.006). Both fesoterodine (< 0.001) and solifenacin (< 0.001) significantly delayed small-intestinal transit compared with placebo. Similarly, the difference between fesoterodine (LS mean change from baseline of 7.4 h) and solifenacin (LS mean change from baseline of 4.5 h) in the t1/2 for ascending colonic emptying was not statistically significant (= 0.061). However, both fesoterodine (< 0.001) and solifenacin (= 0.020) delayed ascending colonic emptying relative to placebo.

Table 2.   Effects on gastrointestinal transit (intention-to-treat population)
ParameterPlacebo (n = 12)Fesoterodine 8 mg (n = 25)Solifenacin 10 mg (n = 23)
  1. aLeast-squares means were calculated from an ancova model, with treatment group as a fixed effect and baseline value, age, and body-mass index as covariates.

  2. *P value for difference in LS mean change from baseline to treatment for SOLI vs PBO; P value for difference in LS mean change from baseline to treatment for FESO vs PBO; P value for difference in LS mean change from baseline to treatment for FESO vs SOLI.

  3. CI=confidence interval, FESO = fesoterodine, GC24 = geometric center of counts at 24 h, GC48 = geometric center of counts at 48 h, PBO = placebo; SOLI = solifenacin; t½ = half-time.

Gastric emptying rate, t1/2 (min)
 Baseline mean (SD)114.2 (27.9)129.8 (32.0)122.6 (21.0)
 Treatment mean (SD)112.9 (22.0)145.0 (32.6)127.5 (35.5)
 LS mean change d 12 (95% CI)a−3.9 (−18.9, 11.3)17.0 (6.6, 27.3)4.3 (−6.4, 15.0)
 Difference in LS means (95% CI)8.2 (−10.0, 26.4)20.8 (2.5, 39.2)12.6 (−2.2, 27.4)
 P value0.368*0.0270.094
Colonic filling at 6 h (%)
 Baseline mean (SD)59.8 (30.5)39.9 (30.6)46.3 (31.7)
 Treatment mean (SD)69.6 (25.9)7.8 (16.3)24.1 (23.7)
 LS mean change d 12 (95% CI)a18.9 (8.1, 29.6)−36.8 (−44.2, −29.5)−21.8 (−29.3, −14.2)
 Difference in LS means (95% CI)−40.6 (−53.7, −27.6)−55.7 (−68.8, −42.6)−15.1 (−25.6, −4.6)
 P value<0.001*<0.0010.006
Ascending colonic emptying rate, t1/2(hours)
 Baseline mean (SD)15.4 (8.3)12.8 (5.1)15.3 (9.3)
 Treatment mean (SD)14.8 (6.2)21.1 (5.5)19.2 (6.2)
 LS mean change d 12–14 (95% CI)a0.1 (−2.9, 3.2)7.4 (5.3, 9.5)4.5 (2.4, 6.7)
 Difference in LS means (95% CI)4.4 (0.7, 8.1)7.3 (3.6, 10.9)2.9 (−0.1, 5.9)
 P value0.020*<0.0010.061
GC24 (score of 1 to 5; primary endpoint)
 Baseline mean (SD)2.5 (1.0)2.4 (0.7)2.4 (0.9)
 Treatment mean (SD)2.5 (1.1)2.0 (0.8)1.9 (0.5)
 LS mean change d 13–14 (95% CI)a0.07 (−0.32, 0.45)−0.44 (−0.71, −0.17)−0.49 (−0.77, −0.21)
 Difference in LS means (95% CI)−0.56 (−1.03, −0.09)−0.51 (−0.97, −0.04)0.05 (−0.33, 0.43)
 P value0.020*0.0330.789
GC48 (score of 1 to 5)
 Baseline mean (SD)4.0 (0.9)3.7 (0.8)3.8 (1.1)
 Treatment mean (SD)3.7 (1.1)3.6 (0.9)3.1 (0.8)
 LS mean change d 14 (95% CI)a−0.24 (−0.67, 0.19)−0.25 (−0.54, 0.05)−0.65 (−0.95, −0.34)
 Difference in LS means (95% CI)−0.41 (−0.93, 0.11)−0.01 (−0.52, 0.51)0.40 (−0.02, 0.82)
 P value0.122*0.9760.063
GC48 minus GC24
 Baseline mean (SD)1.5 (0.9)1.4 (0.8)1.4 (0.7)
 Treatment mean (SD)1.2 (0.7)1.6 (0.7)1.2 (0.6)
 LS mean change d 14 (95% CI)a−0.28 (−0.66, 0.10)0.18 (−0.09, 0.44)−0.16 (−0.43, 0.12)
 Difference in LS means (95% CI)0.12 (−0.35, 0.59)0.46 (−0.01, 0.92)0.34 (−0.04, 0.72)
 P value0.613*0.0520.078

For the GC24 (primary endpoint), the LS mean change from baseline to treatment was 0.07 for the placebo group, −0.44 for the fesoterodine group, and −0.49 for the solifenacin group (Table 2). The difference between the fesoterodine and solifenacin groups was not statistically significant (= 0.789), but fesoterodine (= 0.033) and solifenacin (= 0.020) significantly reduced GC24 vs placebo. For GC48, the LS mean decrease from baseline was less for placebo (−0.24) and fesoterodine (−0.25) than for solifenacin (−0.65). The LS mean difference between fesoterodine and solifenacin for GC48 approached statistical significance (= 0.063); each drug effect was not significant vs placebo (= 0.976 and = 0.122, respectively). There were no significant differences in the LS mean change from baseline in GC48 minus GC24 between the placebo (−0.28), fesoterodine (0.18), and solifenacin (−0.16) groups (all > 0.05; Table 2).

At baseline, colonic filling at 6 h was associated with GC24 for solifenacin (r = 0.57, = 0.005), but not for fesoterodine (r = −0.17, = 0.42) or placebo (r = −0.05, = 0.89); the overall association was not significant (r = 0.18, = 0.16). The treatment-associated change in colonic filling at 6 h was associated with the corresponding change in GC24 for all subjects (r = 0.35, = 0.007), but was not associated with the corresponding change in GC24 for any drug [solifenacin (r = 0.38, = 0.08), fesoterodine (r = 0.10, = 0.63), or placebo (r = 0.45, = 0.14)]. Taken together, these data suggest a modest association between colonic filling at 6 h and GC24 at baseline in the solifenacin group. However, the treatment-associated change in colonic filling at 6 h does not significantly or substantially contribute to the corresponding change in GC24.

Bowel function

The LS mean changes from baseline in the number of stools per day and scores for the ease of stool passage were similar for the placebo, fesoterodine, and solifenacin groups (all > 0.05; Table 3). However, the LS mean change from baseline in the Bristol Stool Form score declined by 0.45 units (reflecting harder stools) with solifenacin, but increased by 0.16 units (reflecting softer stools) with fesoterodine; only the difference between fesoterodine and solifenacin was significant (= 0.010). The proportion of bowel movements with satisfaction declined with fesoterodine, but increased with solifenacin; only the difference between placebo and solifenacin was significant (= 0.004; Table 3). At baseline, stool consistency was correlated with colonic transit (GC24: Spearman = 0.30, = 0.023; GC48: Spearman = 0.33, = 0.011). Moreover, the change (post baseline minus baseline) in stool consistency was correlated with the corresponding change in GC24 (= 0.29, = 0.026) and GC48 (= 0.25, = 0.06).

Table 3.   Effects on bowel habits (intention-to-treat population)
ParameterPlacebo (n = 12)Fesoterodine 8 mg (n = 25)Solifenacin 10 mg (n = 22)
  1. aLeast-squares means were calculated from an ancova model, with treatment group as a fixed effect and baseline value, age, and body-mass index as covariates.

  2. bStool consistency score of 1 = hard lumps, 2 = lumpy sausage, 3 = cracked sausage, 4 = smooth sausage (ideal), 5 = soft lumps, 6 = mushy, and 7 = watery.

  3. cScore of 1 = manual disimpaction, 2 = enema needed, 3 = straining needed, 4 = normal, 5 = urgent without pain, 6 = urgent with pain, and 7 = incontinent.

  4. dProportion of stools that you felt your bowel was completely emptied.

  5. *P value for difference in LS mean change from baseline to treatment for SOLI vs PBO; P value for difference in LS mean change from baseline to treatment for FESO vs PBO; P value for difference in LS mean change from baseline to treatment for FESO vs SOLI. CI = confidence interval, FESO = fesoterodine, PBO = placebo; SOLI = solifenacin.

Number of stools/day
 Baseline mean (SD)1.25 (0.64)1.15 (0.70)1.26 (0.64)
 Treatment mean (SD)1.06 (0.42)0.93 (0.40)1.11 (0.50)
 LS mean change (95% CI)a−0.16 (−0.42, 0.09)−0.26 (−0.44, −0.08)−0.12 (−0.30, 0.07)
 Difference in LS means (95% CI)0.05 (−0.27, 0.37)−0.09 (−0.41, 0.22)−0.14 (−0.40, 0.12)
 P value0.765*0.5510.279
Bristol Stool Scale score/dayb
 Baseline mean (SD)3.86 (0.88)3.54 (0.88)3.47 (1.19)
 Treatment mean (SD)3.29 (1.11)3.66 (1.15)3.02 (1.06)
 LS mean change (95% CI)a−0.33 (−0.77, 0.11)0.16 (−0.16, 0.49)−0.45 (−0.79, −0.12)
 Difference in LS means (95% CI)−0.13 (−0.68, 0.43)0.49 (−0.06, 1.05)0.62 (0.15, 1.08)
 P value0.657*0.0820.010
Ease of stool passage score/dayc
 Baseline mean (SD)3.99 (0.03)3.95 (0.27)3.77 (0.73)
 Treatment mean (SD)3.97 (0.10)3.90 (0.40)3.83 (0.71)
 LS mean change (95% CI)a0.002 (−0.16, 0.16)−0.020 (−0.14, 0.10)−0.002 (−0.12, 0.12)
 Difference in LS means (95% CI)−0.004 (−0.20, 0.19)−0.02 (−0.22, 0.18)−0.02 (−0.19, 0.15)
 P value0.967*0.8260.834
Proportion of stools with satisfaction/dayd
 Baseline mean (SD)0.97 (0.10)0.95 (0.15)0.85 (0.30)
 Treatment mean (SD)0.81 (0.32)0.88 (0.25)0.93 (0.23)
 LS mean change (95% CI)a−0.13 (−0.23, −0.04)−0.04 (−0.11, 0.03)0.05 (−0.02, 0.12)
 Difference in LS means (95% CI)0.18 (0.06, 0.30)0.09 (−0.03, 0.21)−0.09 (−0.19, 0.01)
 P value0.004*0.1360.082

Safety

Treatment with fesoterodine or solifenacin was well-tolerated. Treatment-related AEs occurred in 42% of the subjects in the placebo group, 76% of those in the fesoterodine group, and 64% of those in the solifenacin group (Table 4), with all reported AEs mild or moderate in nature. The most frequently reported treatment-related AE was dry mouth (placebo, 0%; fesoterodine, 52%; solifenacin, 32%). No serious AEs were reported, and no subject discontinued treatment because of AEs. No clinically significant laboratory or vital sign abnormalities were recorded during the study.

Table 4.   Most frequently reported treatment-related adverse events
 Placebo (n = 12)Fesoterodine 8 mg (n = 25)Solifenacin 10 mg (n = 22)
  1. AE = adverse event.

Subjects with any all-causality AEs, n (%)6 (50)22 (88)15 (68)
Subjects with treatment-related AEs, n (%)5 (42)19 (76)14 (64)
 Dry mouth013 (52)7 (32)
 Headache3 (25)10 (40)2 (9)
 Abdominal distension003 (14)
 Back pain003 (14)
 Oropharyngeal pain01 (4)3 (14)

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Subjects
  6. Results
  7. Discussion
  8. Acknowledgments
  9. Funding
  10. Disclosures
  11. Author contributions
  12. References

The primary findings of this study are that the non-selective antimuscarinic fesoterodine and the selective antimuscarinic solifenacin delayed small-intestinal transit and colonic transit (GC24) in healthy women. The fesoterodine induced delay in gastric emptying is modest and unlikely to be of clinical significance. Fesoterodine also delayed the ascending colonic emptying rate, whereas solifenacin also increased stool hardness and tended to delay colonic transit at 48 h (GC48). Taken together with previous study results, these observations increase our understanding of the effects of muscarinic antagonists on and the muscarinic regulation of gastrointestinal transit in humans. In particular, they suggest that the small intestine is more susceptible to the effects of muscarinic antagonists than the colon.

The delay in small-intestinal transit seen with the selective antimuscarinic solifenacin in this study is supported by previously published results for the M3-selective muscarinic antagonist darifenacin ER (7.5 and 15 mg once daily).11 In contrast, the delay in small-intestinal transit observed with the non-selective antimuscarinic fesoterodine was not seen in previously reported results for the non-selective antimuscarinic tolterodine ER (4 mg once daily).10 However, a higher dose of fesoterodine (8 mg once daily) was used in this study, complicating this comparison. Furthermore, the fact that fesoterodine delivers its only active metabolite 5-HMT with less variability and higher bioavailability than tolterodine ER 4 mg must also be considered.14 These variables may explain the higher incidence of dry mouth and constipation with fesoterodine 8 mg than with tolterodine ER 4 mg in previous studies.22,23

Of interest, both fesoterodine and solifenacin delayed the GC24 for colonic transit, whereas solifenacin also tended to delay the GC48. As the GC24 is measured 24 h after the radioactive meal is administered, it is also potentially influenced by small-intestinal transit because the indium capsule used to measure colonic transit takes longer to travel to the colon when small-intestinal transit is delayed. Hence, it is conceivable that the lower GC24 after treatment may reflect not only delayed colonic but also delayed small-intestinal transit. At baseline, percentage colonic filling at 6 h was associated with GC24 for solifenacin only, but not for fesoterodine or placebo; this association is likely due to chance alone. However, the treatment-associated change in percentage colonic filling at 6 h was not associated with the corresponding change in GC24 for any drug. Taken together these observations suggest that the treatment-associated change in percentage colonic filling at 6 h, which is a surrogate marker for small-intestinal transit, does not significantly or substantially contribute to the corresponding change in GC24 for individual drugs. In contrast with fesoterodine, solifenacin also tended to delay the GC48, which reflects delayed colonic, predominantly left colonic, transit.

As demonstrated previously, stool consistency is correlated with colonic transit.10,11,24 However, the observed correlation between colonic transit and stool consistency in the present study was weaker (correlation coefficient of approximately 0.3) than observed previously in irritable bowel syndrome (correlation coefficient of approximately 0.6),25 likely because patients with irritable bowel syndrome have a wider range of colonic transit. Most studies evaluating the relationship between colonic transit and stool consistency assessed these parameters at one point in time. Hence, those studies demonstrated an association between colonic transit and stool consistency, but did not clarify cause and effect. Fluid infusion into the right colon accelerates colonic transit and reduces stool consistency.26 Extending those findings, our observations demonstrate that even lesser alterations in colonic transit alter stool consistency. Relative to baseline, solifenacin increased stool hardness to a greater extent than fesoterodine. The mean reduction in stool consistency with solifenacin (decrease in Bristol Stool Scale score of 0.45 units) is smaller than the 1-unit change that is traditionally regarded as clinically significant. Allowing for differences in drug doses, study duration, study population, and the more refined assessment of bowel habits in this trial, the finding that fesoterodine did not affect bowel habits is in contrast with a meta-analysis of randomized placebo-controlled trials in which fesoterodine was associated with an increased risk of constipation (OR = 2.07, 95% CI: 1.28–3.35).6 In that meta-analysis, the number needed to harm (i.e., develop constipation) is 38 for fesoterodine and 22 for solifenacin, i.e., similar to our data regarding solifenacin’s effects on stool consistency and colonic transit the risk of constipation was higher for solifenacin than fesoterodine.

Although the effects of solifenacin on stool frequency and ease of passage were not significant, it is conceivable that these effects on stool consistency may be clinically significant and aggravate symptoms in subjects with pre-existing constipation. Indeed, 3 of 1158 patients treated with solifenacin (10 mg daily) in four 12-week, double-blind, clinical trials had serious intestinal AEs (fecal impaction, n = 1; colonic obstruction, n = 1; and intestinal obstruction, n = 1).27 A case report of probable solifenacin-induced intestinal pseudo-obstruction also has been described.28 Consideration should be given to using a lower dose of solifenacin in patients with symptoms of constipation. In contrast, the effect of M3-selective muscarinic antagonism on colonic transit might be of interest in the treatment of gut disease characterized by morbidly rapid colonic transit, such as irritable bowel syndrome. Of note, previously published data support the role of an exaggerated muscarinic-receptor–mediated pro-inflammatory cytokine (IL-6) response in irritable bowel syndrome.29

Solifenacin delays small intestinal and colonic transit, which are accelerated in some patients with diarrhea-predominant irritable bowel syndrome (IBS). Hence, it is conceivable that solifenacin may be useful, pending trials, for patients with diarrhea-predominant IBS. These trials should compare the effects of solifenacin on gastrointestinal transit and symptoms to placebo and to hyoscine, an anticholinergic agent, which has been demonstrated to be efficacious for IBS in older studies.30,31 Compared to the effects of alosetron in IBS, solifenacin has greater effects on small intestinal and lesser effects on colonic transit in healthy subjects.32 Hence, one potential advantage of using solifenacin to reduce exaggerated intestinal contractility is that this drug may be less likely than alosetron to cause constipation, particularly in patients who do not have markedly accelerated colonic transit.

Limitations of this study include the small number of healthy women evaluated in each treatment group, the possibility of intra-subject variation in gastrointestinal transit during different phases of the menstrual cycle,33 and the possibility of inter-subject variation in small-intestinal transit measurements,25 with greater variation demonstrated in women than in men.34 In addition, Cremonini and colleagues demonstrated that GC24 values varied by more than one unit in 37% of healthy subjects on repeat testing at 3 weeks, whereas GC48 values varied in 26% of subjects.19 This variation is likely due to biological differences among healthy individuals and not the assessment technique used.35 However, little inter- and intra-subject variation has been demonstrated for scintigraphic assessment of colonic transit in healthy individuals over a period of 14 days.25

In summary, the results of this study suggest that the small intestine is more susceptible to the effects of muscarinic antagonists than the colon, fesoterodine has more pronounced effects on small-intestinal transit than solifenacin, and solifenacin has more pronounced effects on colonic transit than fesoterodine in healthy women; the latter finding may explain why solifenacin, but not fesoterodine, increases stool hardness.

Acknowledgments

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Subjects
  6. Results
  7. Discussion
  8. Acknowledgments
  9. Funding
  10. Disclosures
  11. Author contributions
  12. References

This study was funded by Pfizer Inc. The authors had complete access to all data and had final control over the content, review, and submission of the manuscript. Writing support was provided by Patricia B. Leinen, PhD, and Colin Mitchell, PhD, at Complete Healthcare Communications, Inc., and was funded by Pfizer Inc.

Disclosures

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Subjects
  6. Results
  7. Discussion
  8. Acknowledgments
  9. Funding
  10. Disclosures
  11. Author contributions
  12. References

Adil E. Bharucha owns no stocks or shares in Pfizer. Hitoshi Isowa and Shintaro Hiro are employees of Pfizer Japan Inc. Zhonghong Guan is an employee of Pfizer Inc.

Author contributions

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Subjects
  6. Results
  7. Discussion
  8. Acknowledgments
  9. Funding
  10. Disclosures
  11. Author contributions
  12. References

AB was the principal investigator for the study and contributed to study design and concept, data analysis and interpretation, and manuscript preparation, critical revision, and final approval; HI, SH, and ZG contributed to study design and concept, data analysis and interpretation, and manuscript preparation, critical revision, and final approval.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Subjects
  6. Results
  7. Discussion
  8. Acknowledgments
  9. Funding
  10. Disclosures
  11. Author contributions
  12. References