title: Effect of vitamin K2 on the anticoagulant activity of warfarin during the perioperative period of catheter ablation: Population analysis of retrospective clinical data.
abstract: 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  Catheter ablation is a non-medication therapy for atrial fibrillation, and during the procedure, warfarin is withdrawn in the preoperative period to prevent the risk of bleeding.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 K2 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 K2 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 K2, and the indirect response model was used to investigate the relationship between plasma concentration and the pharmacodynamic response of warfarin and vitamin K2. Since no plasma concentration data for warfarin and vitamin K2 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 K2 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 K2 should be administered with care and that more than 20 mg is unnecessary in the preoperative period of catheter ablation.
authors: Department of Clinical Pharmacology and Therapeutics, Kyoto University Hospital, Sakyo-ku, Japan ; Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Japan.
authors: Zhi
authors: Z
authors: Zhou
authors: Department of Clinical Pharmacology and Therapeutics, Kyoto University Hospital, Sakyo-ku, Japan ; Department of Clinical Pharmacy and Education, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto Japan.
authors: Ikuko
authors: 0000-0001-9517-5628
authors: I
authors: Yano
authors: Department of Clinical Pharmacology and Therapeutics, Kyoto University Hospital, Sakyo-ku, Japan.
authors: Sumiko
authors: S
authors: Odaka
authors: Department of Clinical Pharmacology and Therapeutics, Kyoto University Hospital, Sakyo-ku, Japan.
authors: Yosuke
authors: Y
authors: Morita
authors: Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Sakyo-ku, Japan.
authors: Satoshi
authors: S
authors: Shizuta
authors: Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Sakyo-ku, Japan.
authors: Mamoru
authors: M
authors: Hayano
authors: Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Sakyo-ku, Japan.
authors: Takeshi
authors: T
authors: Kimura
authors: Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Japan.
authors: Akinori
authors: A
authors: Akaike
authors: Department of Clinical Pharmacology and Therapeutics, Kyoto University Hospital, Sakyo-ku, Japan.
authors: Ken-Ichi
authors: K
authors: Inui
authors: Department of Clinical Pharmacology and Therapeutics, Kyoto University Hospital, Sakyo-ku, Japan.
authors: Kazuo
authors: K
authors: Matsubara
keywords: Catheter ablation; INR; NONMEM; Pharmacodynamics; Vitamin K2; Warfarin