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.
de Mey
Christian
C
Applied Clinical Pharmacology Services, Philippsring 11, D-55252, Mainz-Kastel, Germany. C.deMey@ACPS-Network.com
Mateva
Lyudmila
L
Krastev
Zahariy
Z
Sachse
Richard
R
Wood
Nolan
N
Malhotra
Bimal
B
D000293:Adolescent; D000328:Adult; D000368:Aged; D001559:Benzhydryl Compounds / Q000009:adverse effects / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics* / Q000652:urine; D001711:Biotransformation; D003408:Cresols / Q000097:blood / Q000378:metabolism / Q000652:urine; D006207:Half-Life; D048550:Hepatic Insufficiency / Q000378:metabolism; D006801:Humans; D008103:Liver Cirrhosis / Q000097:blood / Q000378:metabolism* / Q000652:urine; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D018727:Muscarinic Antagonists / Q000009:adverse effects / Q000493:pharmacokinetics*; D011355:Prodrugs / Q000009:adverse effects / Q000493:pharmacokinetics*; D012720:Severity of Illness Index; D053201:Urinary Bladder, Overactive / Q000188:drug therapy; D055815:Young Adult
C109909:5-hydroxymethyl tolterodine; D001559:Benzhydryl Compounds; D003408:Cresols; D018727:Muscarinic Antagonists; D011355:Prodrugs; C526675:fesoterodine