THE EFFECT OF ORLISTAT ON THE PHARMACOKINETICS AND PHARMACODYNAMICS OF WARFARIN IN HEALTHY-VOLUNTEERS

To assess the effect of orlistat on the pharmacokinetics and pharmacod ynamics of warfarin, a third-party blind, placebo-controlled, randomiz ed, two-way crossover study was performed in 12 healthy volunteers. Ea ch participant received single 30-mg oral doses of racemic warfarin so dium (Coumadin; DuPont Pharma, Wilmington, DE) administered on the ele venth day of treatment with 120 mg orlistat (treatment A) and placebo (treatment B) three times a day for 16 days; the two treatments were s eparated by a 3-week washout period. Serial blood samples were collect ed before and at appropriate intervals after each dose of warfarin to determine plasma concentrations of R-warfarin and S-warfarin and blood prothrombin time (PT) and plasma Factor VII concentration. In additio n, serum concentrations of vitamin K-1 and its epoxide and of osteocal cin and its undercarboxylated form were measured before breakfast on d ays -7, 1, 4, 6, and 10. Equivalent results between treatments with or listat and placebo were found with regard to all pharmacokinetic param eters of R- and S-warfarin (except for time to maximum concentration o f R-warfarin). Pharmacodynamic parameters of warfarin (PT and Factor V II) and vitamin K nutritional status parameters (ratios of Vitamin K-1 to vitamin K-1 epoxide and undercarboxylated osteocalcin to osteocalc in) also were unaltered by orlistat. Orlistat administered at doses of 120 mg three times daily did not significantly alter the pharmacokine tics and pharmacodynamics of a single 30-mg oral dose of warfarin in h ealthy volunteers.