The pharmacokinetic profile of fesoterodine 8 mg with daytime or nighttime dosing

Abstract

Purpose

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 $AU{C_\infty }$ 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 $AU{C_\infty }$ and C_max ratios of 5-HMT were 93 and 79%, respectively; 90% confidence intervals (CIs) indicated equivalence for $AU{C_\infty }$ 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_½) 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.