Differential effects of selective and non-selective muscarinic antagonists on gastrointestinal transit and bowel function in healthy women

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 6h), colonic transit [geometric center at 24h (GC24; primary endpoint) and 48h (GC48)], and bowel habits were assessed by scintigraphy and bowel diaries before and after randomization to fesoterodine 8mg, solifenacin 10mg, or placebo (2:2:1) for 14days. 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 t_1/2vs placebo (17.0min; P=0.027), and (iii) fesoterodine and solifenacin delayed small-intestinal (-36.8% and -21.8%, respectively, P<0.001 vs placebo) and colonic transit (GC24: -0.44 and -0.49, respectively, P<0.05 vs placebo; GC48: -0.25 and -0.65, respectively, P>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).