Tegaserod coadministration does not alter the pharmacokinetics of theophylline in healthy subjects

Tegaserod (HTF 919), a selective 5-HT4 receptor partial agonist, is in deve lopment for the treatment of functional gastrointestinal motility disorders . Tegaserod has been found to inhibit cytochrome P-450 (CYP) 1A2, for which theophylline is a protoype substrate. This study was designed to assess th e effect of tegaserod on the single-dose pharmacokinetic and safety profile of theophylline. Eighteen subjects were enrolled in a randomized, open-lab el, two-period crossover study. After an overnight fast, subjects were rand omized to receive one of two treatments: (1) a single dose of controlled-re lease formulation of theophylline (Theo-Dur (R), 600 mg) on day 1 or (2) a single dose of tegaserod (6 mg) on day 1, concomitant administration of teg aserod (6 mg) and theophylline (600 mg) on the morning of day 2, followed b y an additional dose of tegaserod (6 mg) 12 hours later. Four to 10 days la ter, the subjects received the alternative treatment regimen. The pharmacok inetic parameters of theophylline, including AUC, C-max, and t(1/2 lambdaz) , were similar for both treatment regimens, although the t(max) of theophyl line was statistically different between the treatments. Except for a decre ase in partial metabolic formation clearance from theophylline to 1-methylu ric acid, which is unlikely to be clinically relevant, there were no statis tically significant differences in renal clearance of theophylline and part ial metabolic formation clearances following the combined treatment compare d with theophylline alone. The results of the current study indicate that n o dose adjustment is required when drugs metabolized via CYP1A2 are coadmin istered with tegaserod. (C) 2001 the American College of Clinical Pharmacol ogy.