This study assessed the pharmacokinetic profiles of administering tegaserod (HTF 919) at different time intervals with respect to a meal. It was a randomized, open-label, two-phase, five-period crossover study. In the first phase, 18 healthy subjects received a single 12 mg oral dose of tegaserod administered either 30 or 15 minutes prior to the start of the 600-calorie, fat-rich breakfast. In the second phase, subjects received a single 12 mg oral dose of tegaserod 1 minute before, 2.5 hours after the start of meal, or with a continued 4-hour postdose fast. Safety assessment and plasma samples for the determination of drug concentration were obtained for 24 hours postdose. Noncompartmental analysis results indicated that the AUC of tegaserod was reduced by almost half under fed conditions compared to the fasted condition. Exploratory analyses were implemented to further investigate the absorption characteristics of tegaserod under different fed conditions. A numerical deconvolution approach was used to obtain the tegaserod oral absorption versus time profiles under both fasted and fed conditions. The tegaserod oral absorption versus time profiles were then fitted by NONMEM to a model containing two absorption phases. Based on the absorption analyses, we found that the reduction in the bioavailability of tegaserod under fed conditions was primarily due to a decrease in the extent of absorption and less so to a decrease in the absorption rate(s). Therefore, although the timing of administration of food does not appear to significantly alter the pharmacokinetics of tegaserod, the administration of food reduces the AUC by approximately 50%.

Tegaserod (HTF 919), a selective 5-HT4 receptor partial agonist with promotile activity throughout the gastrointestinal tract, is in development for the treatment of irritable bowel syndrome. In an open-label, parallel-group study, the pharmacokinetics of a single 12-mg oral dose of tegaserod in patients with severe renal insufficiency requiring hemodialysis were compared with data obtained from healthy subjects matched for age, weight, height, and gender (n = 10, both). The pharmacokinetics of tegaserod were similar in both groups (AUC(0h-tz), ng.h/ml: 14.6 +/- 8.5 vs. 14.3 +/- 7.1; Cmax, ng/ml: 4.6 +/- 2.3 vs. 5.1 +/- 2.2; tmax, h: 1.0, for both). Tegaserod had similar tolerability in renally impaired patients and healthy volunteers, with adverse events largely related to the gastrointestinal pharmacological actions of the drug. Therefore, no dose adjustment of tegaserod is necessary for patients with renal insufficiency.

Clinical Pharmacology & Therapeutics (1999) 65, 203–203; doi: