Effects of Hepatic Dysfunction on the Single-Dose Pharmacokinetics of Fesoterodine

Fesoterodine, a new antimuscarinic for the treatment of overactive bladder, is rapidly and extensively hydrolyzed by nonspecific esterases to its principal active moiety, 5-hydroxymethyl tolterodine (5-HMT). The elimination of 5-HMT involves metabolism and renal excretion. The plasma and urinary pharmacokinetics of 5-HMT and its inactive carboxy (SPM 5509), N-desisopropyl (SPM 7789), and carboxy-N-desisopropyl (SPM 7790) metabolites were investigated after a single oral dose of 8 mg of fesoterodine in 8 male subjects with moderate hepatic cirrhosis (Child-Turcotte-Pugh class B) and 8 matched healthy controls. The estimated mean ratios (95% confidence interval) of the area under the curve extrapolated to infinity after dosing (AUC 0-∞ ), cumulative urinary excretion up to 48 hours after dosing (Ae 0-48 ), maximum observed concentration (C max ), and apparent terminal disposition half-life (t 1/2 ) of 5-HMT for cirrhotic and healthy subjects were 2.2 (1.5-3.1), 2.5 (1.7-3.8), 1.4 (1.0-1.9), and 1.1 (0.8-1.3), respectively. In subjects with hepatic cirrhosis, AUC 0-∞ and Ae 0-48 of 5-HMT increased approximately 2-fold; the increase in C max was smaller, and t 1/2 was unaffected. AUC and C max of the inactive carboxy metabolites, SPM 5509 and SPM 7790, were reduced reciprocally by about 50%, whereas exposure to the dealkylated metabolite, SPM 7789, increased about 2-fold. Fesoterodine 8 mg was equally well tolerated in both groups. The results indicate that moderate hepatic cirrhosis reduces 5-HMT clearance, with an apparent effect on the carboxylation pathway and not on dealkylation.