Effect of vitamin K(2) on the anticoagulant activity of warfarin during the perioperative period of catheter ablation: Population analysis of retrospective clinical data

BACKGROUND: Catheter ablation is a non-medication therapy for atrial fibrillation, and during the procedure, warfarin is withdrawn in the preoperative period to prevent the risk of bleeding. In case of emergency, vitamin K(2) can be intravenously administered to antagonize the anticoagulant activity of warfarin. The aims of this study were to conduct population pharmacokinetic/pharmacodynamic modeling for retrospective clinical data and to investigate the effect of vitamin K(2) on the anticoagulant activity of warfarin in the perioperative period of catheter ablation. METHODS: A total of 579 international normalized ratio (INR) values of prothrombin time from 100 patients were analyzed using the nonlinear mixed-effects modeling program NONMEM. A 1-compartment model was adapted to the pharmacokinetics of warfarin and vitamin K(2), and the indirect response model was used to investigate the relationship between plasma concentration and the pharmacodynamic response of warfarin and vitamin K(2). Since no plasma concentration data for warfarin and vitamin K(2) were available, 3 literally available pharmacokinetic parameters were used to simultaneously estimate 1 pharmacokinetic parameter and 5 pharmacodynamic parameters. RESULTS: The population parameters obtained not only successfully explained the observed INR values, but also indicated an increase in sensitivity to warfarin in patients with reduced renal function. Simulations using these parameters indicated that vitamin K(2) administration of more than 20 mg caused a slight dose-dependent decrease in INR on the day of catheter ablation and a delayed INR elevation after warfarin re-initiation. CONCLUSIONS: A pharmacokinetic/pharmacodynamic model was successfully built to explain the retrospective INR data during catheter ablation. Simulation studies suggest that vitamin K(2) should be administered with care and that more than 20 mg is unnecessary in the preoperative period of catheter ablation.