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Effects of Hepatic Dysfunction on the Single‐Dose Pharmacokinetics of Fesoterodine
Author(s) -
Mey Christian,
Mateva Lyudmila,
Krastev Zahariy,
Sachse Richard,
Wood Nolan,
Malhotra Bimal
Publication year - 2011
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1177/0091270010365547
Subject(s) - cmax , pharmacokinetics , tolterodine , metabolite , cirrhosis , chemistry , pharmacology , area under the curve , medicine , urinary system , endocrinology , overactive bladder , alternative medicine , pathology
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.