Influence of food on the pharmacokinetic profile of fesoterodine.
OBJECTIVE
Fesoterodine is a new, once-daily, oral, antimuscarinic agent indicated for the treatment of overactive bladder. It undergoes rapid and extensive metabolism by plasma esterases to form its principal active moiety, 5-hydroxymethyl tolterodine (5-HMT). The sustained-release formulation of fesoterodine delivers 5-HMT with linear, dose-proportional pharmacokinetics (PK) suitable for once-daily dosing. This study was designed for the definitive assessment of the effect of food on 5-HMT PK using the commercial formulation of fesoterodine.


METHODS
In this randomized, open-label, single-dose, 2-way, crossover study, fesoterodine 8 mg was administered orally to healthy subjects in either a fed (after a high-fat, high-calorie breakfast) or fasted state. Blood samples for PK were drawn up to 36 hours after dosing. Primary endpoints for food effect assessment were area under the concentration-versus-time curve up to the last sample (AUC(0-tz)), and maximum plasma concentration (C(max)) for 5-HMT. Adverse events, vital signs, hematology, clinical chemistry, and electrocardiograms were monitored for safety assessment.


RESULTS
A total of 16 healthy male subjects enrolled and completed the study. Mean values of both primary PK parameters of 5-HMT (AUC(0-tz) and C(max)) were approximately 19% higher after fesoterodine administration in the fed versus the fasted state. The upper limits of the corresponding 90% confidence intervals for the "fed/fasted" ratios of AUC(0-tz) (104%, 137%) and C(max) (94%, 149%) were not included in the prespecified acceptance range (80%, 125%) for concluding "no food effect." Secondary PK variables, (i.e. time to maximum plasma concentration terminal elimination half-life and mean residence time), did not differ markedly between the fed and fasted states. Fesoterodine was well tolerated, and adverse events were mild, with no apparent difference in frequency between fed and fasted states.


CONCLUSIONS
The hypothesis of "no food effect" could not be statistically confirmed; however, only modest increases of approximately 19% were observed for C(max) and AUC(0-tz) of 5-HMT. This magnitude of PK effects is unlikely to be of clinical relevance based on Phase 2 and 3 clinical experience with fesoterodine, supporting its administration without regard to meals.
Malhotra
B
B
Pfizer Inc, New York, NY 10017, USA. bimal.k.malhotra@pfizer.com
Sachse
R
R
Wood
N
N
D000293:Adolescent; D000328:Adult; D001559:Benzhydryl Compounds / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D018592:Cross-Over Studies; D005215:Fasting; D005502:Food; D018565:Food-Drug Interactions; D006801:Humans; D008297:Male; D008875:Middle Aged; D018727:Muscarinic Antagonists / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*
D001559:Benzhydryl Compounds; D018727:Muscarinic Antagonists; C526675:fesoterodine