Tolterodine in the treatment of overactive bladder:: Analysis of the pooled Phase II efficacy and safety data

Objectives. To summarize the efficacy and safety of tolterodine from the pooled data of four multicenter, randomized, double-blind, placebo-controlled, dose-ranging, parallel-group Phase II studies in patients with urodynamically proved overactive bladder (detrusor instability or detrusor hyperreflexia) and to analyze the concentration-effect relation. Methods. After a 1-week run-in period to establish baseline values, 319 patients were randomized to receive placebo or tolterodine 0.5, 1, 2, or 4 mg twice daily. Micturition diary and urodynamic variables and subjective urinary symptoms were assessed after 2 weeks of treatment. Patients were classified as "extensive" or "poor" metabolizers of tolterodine on the basis of serum levels of tolterodine. Results. A per-protocol analysis of efficacy in 262 patients showed dose-related improvements in micturition diary and urodynamic variables. A dosage of 4 mg twice daily was, however, associated with an increase in residual urinary volume. The incidence of adverse events (mainly mild or moderate antimuscarinic effects) was comparable between placebo and tolterodine dosages of 2 mg twice daily. No serious drug-related adverse events were observed, and tolterodine had no clinically significant impact on electrocardiographic or laboratory findings. Changes in urodynamic variables were found to be related to the sum of unbound serum concentrations of tolterodine and its major active 5-hydroxymethyl metabolite. In poor and extensive metabolizers of tolterodine, exposure to the sum of these active moieties was similar, and the efficacy and safety profiles were comparable. Conclusions. The results of this pooled data analysis indicate that tolterodine offers an effective treatment for patients with urinary symptoms attributable to overactive bladder. The optimal dosage is 1 to 2 mg twice daily, irrespective of metabolic phenotype. UROLOGY 53: 990-998, 1999. (C) 1999, Elsevier Science Inc. All rights reserved.