Tegaserod Coadministration Does Not Alter the Pharmacokinetics of Theophylline in Healthy Subjects

Abstract

Tegaserod (HTF 919), a selective 5‐HT4 receptor partial agonist, is in development for the treatment of functional gastrointestinal motility disorders. Tegaserod has been found to inhibit cytochrome P‐450 (CYP) 1A2, for which theophylline is a prototype substrate. This study was designed to assess the effect of tegaserod on the single‐dose pharmacokinetic and safety profile of theophylline. Eighteen subjects were enrolled in a randomized, open‐label, two‐period crossover study. After an overnight fast, subjects were randomized to receive one of two treatments: (1) a single dose of controlled‐release formulation of theophylline (Theo‐Dur®, 600 mg) on day 1 or (2) a single dose of tegaserod (6 mg) on day 1, concomitant administration of tegaserod (6 mg) and theophylline (600 mg) on the morning of day 2, followed by an additional dose of tegaserod (6 mg) 12 hours later. Four to 10 days later, the subjects received the alternative treatment regimen. The pharmacokinetic parameters of theophylline, including AUC, Cmax' and t1/2Λz' were similar for both treatment regimens, although the tmax of theophylline was statistically different between the treatments. Except for a decrease in partial metabolic formation clearance from theophylline to 1‐methyluric acid, which is unlikely to be clinically relevant, there were no statistically significant differences in renal clearance of theophylline and partial metabolic formation clearances following the combined treatment compared with theophylline alone. The results of the current study indicate that no dose adjustment is required when drugs metabolized via CYP1A2 are coadministered with tegaserod.