Effects of hepatic dysfunction on the single-dose pharmacokinetics of fesoterodine.

Abstract

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.

• Authors: Christian de Mey, Lyudmila Mateva, Zahariy Krastev, Richard Sachse, Nolan Wood, Bimal Malhotra
• Journal: Journal of clinical pharmacology (J Clin Pharmacol) Vol. 51 Issue 3 Pg. 397-405 (Mar 2011) ISSN: 1552-4604 [Electronic] England
• PMID: 20371737 (Publication Type: Controlled Clinical Trial, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 5-hydroxymethyl tolterodine
• Benzhydryl Compounds
• Cresols
• Muscarinic Antagonists
• Prodrugs
• fesoterodine

Topics

• Adolescent
• Adult
• Aged
• Benzhydryl Compounds (adverse effects, blood, metabolism, pharmacokinetics, urine)
• Biotransformation
• Cresols (blood, metabolism, urine)
• Half-Life
• Hepatic Insufficiency (metabolism)
• Humans
• Liver Cirrhosis (blood, metabolism, urine)
• Male
• Metabolic Clearance Rate
• Middle Aged
• Muscarinic Antagonists (adverse effects, pharmacokinetics)
• Prodrugs (adverse effects, pharmacokinetics)
• Severity of Illness Index
• Urinary Bladder, Overactive (drug therapy)
• Young Adult