Pharmacokinetic profile of fesoterodine.

Article Details

Citation

Malhotra B, Guan Z, Wood N, Gandelman K

Pharmacokinetic profile of fesoterodine.

Int J Clin Pharmacol Ther. 2008 Nov;46(11):556-63.

PubMed ID
19000553 [ View in PubMed
]
Abstract

OBJECTIVE: Fesoterodine is a new antimuscarinic agent for the treatment of overactive bladder. Following oral administration, fesoterodine is rapidly and extensively hydrolyzed by nonspecific esterases to its active moiety: 5-hydroxymethyl tolterodine (5-HMT). The cytochrome P450 (CYP) enzymes are not involved in the formation of 5-HMT; however, CYP2D6 and CYP3A4 provide 2 alternative pathways for further metabolism and inactivation of 5-HMT. MATERIALS: Single oral doses of 4 mg, 8 mg or 12 mg of fesoterodine sustained-release tablets in the fasted state and 8 mg in a fed state. METHODS: This single-center, open-label, randomized, crossover study investigated the effects of fesoterodine in healthy volunteers comprised of CYP2D6 extensive metabolizers (EMs; n = 16) and CYP2D6 poor metabolizers (PMs; n = 8) after either an overnight fast or a high-fat and high-calorie breakfast. Adverse events, vital signs, ECG recordings and laboratory tests were monitored for safety assessment. RESULTS: For the principal active moiety, 5-HMT, the maximum plasma concentration (Cmax), area under the concentration-time curve from time zero to time of last measurable concentration (AUC0-t) and amount excreted in urine (Ae) increased proportionally with dose in both EM and PM subjects. The mean Cmax and AUC0-t in PMs were approximately twice those observed in EMs. CYP2D6 status had no effect on time to reach Cmax (5 h), renal clearance (approximately 250 ml/min), or half-life (approximately 8 h). Fesoterodine was well tolerated at all doses. While the incidence of dry mouth increased from 8 - 12 mg, all occurrences were mild-to-moderate. CONCLUSIONS: Fesoterodine demonstrated a pharmacokinetic (PK) profile that was favorable for once-daily dosing. The systemic exposure to 5-HMT increased proportionally with dose and was about 2-fold higher in PMs compared with EMs. There was no clinically relevant effect of food on the PK of fesoterodine. Fesoterodine was well tolerated at all dose levels studied.

DrugBank Data that Cites this Article

Drug Enzymes
DrugEnzymeKindOrganismPharmacological ActionActions
FesoterodineCytochrome P450 2D6ProteinHumans
Unknown
Substrate
Details
FesoterodineCytochrome P450 3A4ProteinHumans
Unknown
Substrate
Details