The pharmacokinetic profile of fesoterodine 8 mg with daytime or nighttime dosing.
OBJECTIVE
Diurnal variation can affect drug pharmacokinetics. Fesoterodine is a new antimuscarinic drug for the treatment of overactive bladder (OAB). We estimated the relative bioavailability of 5-hydroxymethyl tolterodine (5-HMT), the active metabolite of fesoterodine, following nighttime and daytime administration.


METHODS
In this randomized, open-label, two-period, two-treatment crossover, single-dose study, healthy subjects received daytime and nighttime oral dosing of fesoterodine 8-mg sustained-release tablets, separated by a minimum 60-h washout period. Blood samples for 5-HMT PK determination were collected before dosing and at specified intervals up to 48 h postdose. Safety was assessed by adverse event (AE) reports.


RESULTS
Fourteen subjects completed the study. Plasma concentration versus time profiles (AUC) of 5-HMT were similar for daytime and nighttime dosing. Mean AUC(infinity) 5-HMT values were 47.9 and 51.4 ng h/mL for nighttime and daytime dosing, respectively; the mean time to reach maximum concentration (C(max)) values were 3.9 and 5.0 ng/mL, respectively. Nighttime versus daytime AUC(infinity) and C(max) ratios of 5-HMT were 93 and 79%, respectively; 90% confidence intervals (CIs) indicated equivalence for AUC(infinity) but not for C(max). The median time to reach maximum concentration (T(max)) was 5.0 h for both dosing regimens, and the mean terminal elimination half-life (T((1/2))) was 5.9 and 5.7 h for nighttime and daytime dosing, respectively. Seven treatment-related AEs, most commonly headache, occurred in five subjects.


CONCLUSIONS
The AUC values for daytime and nighttime administration of fesoterodine were equivalent. The 21% reduction in the C(max) for nighttime dosing is unlikely to be clinically relevant. No safety issues were apparent. These results support both daytime and nighttime administration of fesoterodine for OAB treatment.
Malhotra
Bimal K
BK
Pfizer Inc, New York, NY 10017, USA. bimal.k.malhotra@pfizer.com
Crownover
Penelope H
PH
LaBadie
Robert
R
Glue
Paul
P
MacDiarmid
Scott A
SA
D000293:Adolescent; D000328:Adult; D001559:Benzhydryl Compounds / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D001682:Biological Availability; D015992:Body Mass Index; D003408:Cresols / Q000097:blood; D018592:Cross-Over Studies; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics; D003692:Delayed-Action Preparations / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D055870:Drug Chronotherapy; D005260:Female; D005838:Genotype; D006207:Half-Life; D006261:Headache / Q000139:chemically induced; D006801:Humans; D008297:Male; D008875:Middle Aged; D018727:Muscarinic Antagonists / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D013223:Statistics as Topic; D055815:Young Adult
C109909:5-hydroxymethyl tolterodine; D001559:Benzhydryl Compounds; D003408:Cresols; D003692:Delayed-Action Preparations; D018727:Muscarinic Antagonists; C526675:fesoterodine; D019389:Cytochrome P-450 CYP2D6