Fesoterodine Dose Response in Subjects With Overactive Bladder Syndrome
Khullar V, Rovner ES, Dmochowski R, et al.
Urology 2008;71:839–843.
This article reports the pooled analysis of data from 2 fixed-dose, randomized, placebo-controlled, phase III trials on the newest overactive bladder (OAB) drug, fesoterodine, that may become available in North America within a year. Eligible subjects (adult men and women with OAB syndrome) were randomized to fesoterodine 4 mg or 8 mg or placebo for 12 weeks. The purpose of this analysis was to evaluate the 2 doses of fesoterodine for dose-dependent increases in efficacy, safety, and tolerability.
Voiding parameters, including the time of each void, voided volume, urgency, and urgency urinary incontinence (UUI) episodes recorded on pre- and posttreatment 3-day bladder diaries were the primary measures of efficacy. Primary end points were changes in number of voids and mean number of UUI episodes per 24 hours, and treatment response derived from a 4-point treatment benefit scale. Secondary end points included changes in mean voided volume, daytime and nighttime voiding frequency, urgency episodes, and continent days per week.
Statistically significant improvements on all efficacy end points were achieved in both fesoterodine-treated groups compared with placebo at 2 weeks after treatment, and these improvements were sustained throughout the entire 12-week treatment period. Furthermore, the 8-mg fesoterodine treatment group had significantly greater improvement in all diary variables than those receiving fesoterodine 4 mg (P < .05), with the exception of voiding frequency. Adverse events such as dry mouth, constipation, and urinary tract infection were reported more frequently with fesoterodine than with placebo. The incidence of dry mouth was dose dependent and somewhat higher compared with solifenacin, but lower than oxybutynin and darifenacin. The incidence of constipation was relatively low compared with other antimuscarinics.
The study concluded that even though both fesoterodine 4 mg and 8 mg improve OAB symptoms, treatment with fesoterodine 8 mg may achieve superior results. These findings support the added benefit of dose flexibility and individualization with fesoterodine 8 mg. We have not had a new OAB drug come on the market in a few years, and look forward to the release of fesoterodine.
Pharmacological Characterization of a Novel Investigational Antimuscarinic Drug, Fesoterodine, In Vitro and In Vivo
Ney P, Pandita RK, Newgreen DT, et al.
BJU Int 2008;101:1036–1042.
This recently published article sought to characterize the pharmacology of fesoterodine and its active metabolite, SPM 7605, against human muscarinic receptor subtypes, as well as investigate the functional activity of these agents in vitro and in vivo on the rat bladder compared with existing standard agents. Standard drug testing techniques were used to determine the binding affinity to muscarinic acetylcholine receptors. Membrane preparations of Chinese hamster ovary (CHO) cells expressing the human muscarinic receptors M1–M5 were used to determine the binding affinity of test substances. Organ-bath experiments measured the effects of fesoterodine, SPM 7605, oxybutynin, and atropine on rat bladder strip contractions induced by carbachol or electrical field stimulation (EFS). In vivo experiments used cystometry in conscious female rats to measure the effects of fesoterodine and SPM 7605 compared with oxybutynin and atropine.
Clinically relevant key experimental results include the finding that SPM 7605 strongly inhibited radioligand binding at all 5 human muscarinic receptor subtypes with equal affinity, and although fesoterodine had a similar balanced selectivity profile, it was less potent than SPM 7605.
In carbachol-induced rat bladder strip contractions, fesoterodine and SPM 7605 caused a rightward shift of the concentration-response curve with no depression of the maximum. Reductions in EFS-induced contractions were achieved with all compounds and were concentration dependent. The potency of both fesoterodine and SPM 7605 was similar to that of atropine and oxybutynin. In the presence of neostigmine, the potency of fesoterodine was decreased, suggesting that there was esterase activity capable of changing fesoterodine to SPM 7605 in the bladder strips. Therefore, the effects of fesoterodine in vitro were likely partly exerted by the metabolite SPM 7605. In vivo, low doses of fesoterodine and SPM 7605 reduced micturition pressure and increased intercontraction intervals and bladder capacity, but did not affect residual volume.
What are the conclusions? The findings presented in this article confirm the competitive muscarinic antagonist profile of both fesoterodine and its active metabolite, SPM 7605, with SPM 7605 exhibiting greater potency. This benchtop study supports the clinical use of fesoterodine and outlines the expected clinical effects as well as potential side effects. Considering the findings reported in these 2 papers, it is unlikely that there will be any unexpected surprises with fesoterodine, and the benefits of dose flexibility may offer improved efficacy and compliance.