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

Abstract

Background: 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.

Methods: Data from subjects enrolled in double-blind, placebo-controlled phase II and III trials were used for developing longitudinal dose-response models.

Results: 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.

Conclusions: 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.

Trial registration: The phase III trials used in this analysis have been registered at ClinicalTrials.gov (NCT00220363 and NCT00138723).

Figures

Figure 1

Posterior predictive check for change from baseline in number of micturitions after taking placebo or fesoterodine 4 mg, 8 mg, or 12 mg.

Figure 2

Posterior predictive check for change from baseline in number of urgency urinary incontinence (UUI) episodes after taking placebo or fesoterodine 4 mg, 8 mg, or 12 mg.

Figure 3

Posterior predictive check for change from baseline in mean voided volume (MVV) after taking placebo or fesoterodine 4 mg, 8 mg, or 12 mg.

Figure 4

Posterior predictive check (PPC) for the probability of postvoid residual (PVR) urinary volume >100 mL at any time point for women and men and patients aged ≤70 years or >70 years. Circles indicate 10%, 50%, and 90% quantiles per dose; asterisks are observed rates per 1000 simulations.