Silver N, Sandage B, Sabounjian L, Schwiderski U, Harnett M

Indevus Pharmaceuticals Inc, Lexington, MA

Introduction and Objectives: Trospium chloride is a quaternary amine antimuscarinic for the treatment of overactive bladder. A once-daily (QD) extended-release formulation – trospium XR 60 mg – that utilizes both time- and pH-dependent release technologies is currently in development. The objective of this study was to characterize the pharmacokinetics (PK) and compare the relative bioavailability of trospium XR 60 mg when given to healthy subjects in a fasted state (treatment A), in a fed state (treatment B), and when coadministered with a potent antacid (treatment C).

Methods: This was a single-center, single-dose, open-label, randomized, three-period crossover, bioavailability study undertaken in healthy male (n=3) and female (n=9) adult subjects. Subjects were randomized to one of six treatment sequences (ABC, ACB, BAC, BCA, CAB, or CBA), which were separated by washout periods. Each subject received trospium XR 60 mg as a single dose with water at the beginning of each treatment period. During the fed and antacid treatment periods, subjects received a single dose of trospium XR 60 mg 30 min after the consumption of a high-fat meal (at least 50% fat content), or were fasted and then given trospium XR 60 mg 30 min after morning administration of Gaviscon^® Extra Strength Liquid 20 mL, respectively. Treatment comparisons were made versus subjects in the fasted (reference) condition. PK parameters determined included C_max (maximum concentration), T_max (time taken to reach maximum concentration), AUC_(0–24) (area under the concentration–time curve from time zero to 24 h), AUC_(0–∞) (AUC from time zero extrapolated to infinity), AUC_(0–Tlast) (AUC from time zero to time of last measurable concentration), HVD (half-value duration), and t_1/2 (half-life). Similar rates of exposure were defined if the ratios of the point estimates for C_max and AUC_(0–Tlast) were within 80–125%.

Results: The concentration–time curve revealed similar PK profiles for trospium XR in the fasted and antacid conditions. The mean ratios for C_max and AUC_(0–Tlast) differed by no more than 10% and 5%, respectively, in the presence versus the absence of antacid in fasted subjects (Table 1). Median T_max, mean t_1/2, and HVD were also comparable in the fasted and fasted with antacid conditions. Exposure to trospium XR in the fed condition was 35–60% lower than in the fasted condition (Table 1), indicating a significant food effect. Median T_max and mean t_1/2 were comparable between fasted and fed subjects.

Table 1. Statistical comparison of PK parameters versus reference subjects

Conclusions: Trospium XR may be coadministered with antacids without alteration of the PK profile. However, administration of trospium XR with a high-fat meal resulted in lower exposure to trospium XR compared with administration during a fasted state. These data suggest that trospium XR should be taken on an empty stomach but without regard to antacid use.

UroToday.com Coverage of SUFU 2007

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