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Modeling dose-response relationships of the effects of fesoterodine in patients with overactive bladder.

ABSTRACT: Fesoterodine is an antimuscarinic for the treatment of overactive bladder, a syndrome of urgency, with or without urgency urinary incontinence (UUI), usually with increased daytime frequency and nocturia. Our objective was to develop predictive models to describe the dose response of fesoterodine.Data from subjects enrolled in double-blind, placebo-controlled phase II and III trials were used for developing longitudinal dose-response models.The models predicted that clinically significant and near-maximum treatment effects would be seen within 3 to 4 weeks after treatment initiation. For a typical patient with 11 micturitions per 24 hours at baseline, predicted change was -1.2, -1.7, and -2.2 micturitions for placebo and fesoterodine 4 mg and 8 mg, respectively. For a typical patient with 2 UUI episodes per 24 hours at baseline, predicted change was -1.05, -1.26, and -1.43 UUI episodes for placebo and fesoterodine 4 mg and 8 mg, respectively. Increase in mean voided volume was estimated at 9.7 mL for placebo, with an additional 14.2 mL and 28.4 mL for fesoterodine 4 mg and 8 mg, respectively.A consistent dose response for fesoterodine was demonstrated for bladder diary endpoints in subjects with overactive bladder, a result that supports the greater efficacy seen with fesoterodine 8 mg in post hoc analyses of clinical trial data. The dose-response models can be used to predict outcomes for doses not studied or for patient subgroups underrepresented in clinical trials.The phase III trials used in this analysis have been registered at ClinicalTrials.gov (NCT00220363 and NCT00138723).

SUBMITTER: Cardozo L

PROVIDER: S-EPMC2939595 | biostudies-literature | 2010 Aug

REPOSITORIES: biostudies-literature

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Modeling dose-response relationships of the effects of fesoterodine in patients with overactive bladder.

Cardozo Linda L Khullar Vik V El-Tahtawy Ahmed A Guan Zhonghong Z Malhotra Bimal B Staskin David D

BMC urology 20100819

<h4>Background</h4>Fesoterodine is an antimuscarinic for the treatment of overactive bladder, a syndrome of urgency, with or without urgency urinary incontinence (UUI), usually with increased daytime frequency and nocturia. Our objective was to develop predictive models to describe the dose response of fesoterodine.<h4>Methods</h4>Data from subjects enrolled in double-blind, placebo-controlled phase II and III trials were used for developing longitudinal dose-response models.<h4>Results</h4>The ...[more]

PMID: 20723260

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Project description:AimsTo evaluate the efficacy and tolerability of flexible-dose fesoterodine in subjects with overactive bladder (OAB) who were dissatisfied with previous tolterodine treatment.MethodsThis was a 12-week, open-label, flexible-dose study of adults with OAB (> or = 8 micturitions and > or = 3 urgency episodes per 24 h) who had been treated with tolterodine (immediate- or extended-release) for OAB within 2 years of screening and reported dissatisfaction with tolterodine treatment. Subjects received fesoterodine 4 mg once daily for 4 weeks; thereafter, daily dosage was maintained at 4 mg or increased to 8 mg based on the subject's and physician's subjective assessment of efficacy and tolerability. Subjects completed 5-day diaries, the Patient Perception of Bladder Condition (PPBC) and the Overactive Bladder Questionnaire (OAB-q) at baseline and week 12 and rated treatment satisfaction at week 12 using the Treatment Satisfaction Question (TSQ). Safety and tolerability were assessed.ResultsAmong 516 subjects treated, approximately 50% opted for dose escalation to 8 mg at week 4. Significant improvements from baseline to week 12 were observed in micturitions, urgency urinary incontinence episodes, micturition-related urgency episodes and severe micturition-related urgency episodes per 24 h (all p < 0.0001). Approximately 80% of subjects who responded to the TSQ at week 12 reported satisfaction with treatment; 38% reported being very satisfied. Using the PPBC, 83% of subjects reported improvement at week 12 with 59% reporting improvement > or = 2 points. Significant improvements from baseline (p < 0.0001) exceeding the minimally important difference (10 points) were observed in OAB-q Symptom Bother and Health-Related Quality of Life (HRQL) scales and all four HRQL domains. Dry mouth (23%) and constipation (5%) were the most common adverse events; no safety issues were identified.ConclusionFlexible-dose fesoterodine significantly improved OAB symptoms, HRQL, and rates of treatment satisfaction and was well tolerated in subjects with OAB who were dissatisfied with prior tolterodine therapy.

Project description:Overactive bladder (OAB) is a chronic condition affecting both men and women, with prevalence increasing with age. Antimuscarinics form the cornerstone of treatment of OAB. Fesoterodine, a nonselective muscarinic-receptor antagonist, was approved by the US Food and Drug Administration in late 2008 for once daily, oral administration in the treatment of OAB to relieve the symptoms of urinary urge incontinence, urgency, and frequency.The aim of this review was to provide an overview of the mechanism of action of and clinical trial data for fesoterodine, and to discuss the present status of fesoterodine in the management of OAB.The MEDLINE and Google Scholar databases were searched (June 1, 1999-December 1, 2009) using the terms fesoterodine, overactive bladder, and muscarinic antagonists. Full-text articles in English were selected for reference, and articles presenting the mechanism of action, pharmacokinetics, and data from clinical trials were included. The parameters measured were tolerability, efficacy, and health-related quality of life (HRQoL). Trials involving animals and Phase I studies were excluded.The initial literature search yielded 48 papers. A total of 20 articles fulfilled the inclusion criteria. In two 12-week, randomized, multicenter, Phase III clinical trials involving patients with increased micturition frequency and urgency and/or urinary urge incontinence (n = 836 and 1132 in each trial), both fesoterodine 4 and 8 mg were associated with significantly improved symptoms of OAB (frequency of micturition, urgency, and urge incontinence) compared with placebo (P < 0.05). In a post hoc analysis of pooled data of the Phase III trials, HRQoL improved significantly with both doses. In a 12-week, Phase Illb trial, fesoterodine 4 and 8 mg led to treatment satisfaction in ?80% of patients (of 516 enrolled) who were initially unsatisfied with their previous treatment.A review of the literature suggests that fesoterodine is an efficacious and well-tolerated treatment option for patients with OAB.

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Modeling dose-response relationships of the effects of fesoterodine in patients with overactive bladder.

Publications

Modeling dose-response relationships of the effects of fesoterodine in patients with overactive bladder.

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