Pharmacokinetic profile of fesoterodine.
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.


METHODS
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.
Malhotra
B
B
Pfizer Inc, New York, NY 10017, USA. bimal.k.malhotra@pfizer.com
Guan
Z
Z
Wood
N
N
Gandelman
K
K
D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D019540:Area Under Curve; D001559:Benzhydryl Compounds / Q000009:adverse effects / Q000378:metabolism / Q000493:pharmacokinetics*; D003408:Cresols / Q000378:metabolism / Q000493:pharmacokinetics*; D018592:Cross-Over Studies; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism*; D005215:Fasting / Q000378:metabolism; D006207:Half-Life; D006801:Humans; D016014:Linear Models; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D055815:Young Adult
C109909:5-hydroxymethyl tolterodine; D001559:Benzhydryl Compounds; D003408:Cresols; C526675:fesoterodine; D019389:Cytochrome P-450 CYP2D6