Lack of pharmacokinetic interactions between argatroban and warfarin

The potential for pharmacokinetic interactions between argatroban and warfarin was studied. In a randomized, crossover study, healthy volunteers participated in three treatment periods, each separated by a nine-day washout interval. Drug regimens consisted of a single oral 7.5-mg dose of warfarin, intravenous argatroban infused at a rate of 1.25 mug/kg/min for 100 hours, or both. Blood samples were collected at intervals up to 104 hours to determine clearance (CL) and the apparent first-order elimination rate constant (k(el)) for argatroban and the area under the concentration-versus-time curve (AUC) and maximum concentration (C-max) for R- and S-warfarin. An interaction was defined as a >25% difference in the magnitude of the pharmacokinetic values between administration of one drug alone and coadministration with the other agent. Twelve adult subjects were enrolled. The mean CL and k(el) for argatroban administered alone differed by <7% from the mean values when the two drugs were coadministered. When warfarin was administered alone, the mean C-max and AUC of R- and S-warfarin differed from the mean values when the two drugs were coadministered by <10%. Prothrombin time was prolonged comparably when argatroban was administered alone and with warfarin. No deaths or serious adverse events were reported. No significant pharmacokinetic interactions were detected between i.v. argatroban 1.25 mug/kg/min and a single 7.5-mg oral dose of warfarin. Argatroban was well tolerated when administered alone or with warfarin.