title: Determinants of the over-anticoagulation response during warfarin initiation therapy in Asian patients based on population pharmacokinetic-pharmacodynamic analyses.
abstract: To clarify pharmacokinetic-pharmacodynamic (PK-PD) factors associated with the over-anticoagulation response in Asians during warfarin induction therapy, population PK-PD analyses were conducted in an attempt to predict the time-courses of the plasma S-warfarin concentration, Cp(S), and coagulation and anti-coagulation (INR) responses. In 99 Chinese patients we analyzed the relationships between dose and Cp(S) to estimate the clearance of S-warfarin, CL(S), and that between Cp(S) and the normal prothrombin concentration (NPT) as a coagulation marker for estimation of IC50. We also analyzed the non-linear relationship between NPT inhibition and the increase in INR to derive the non-linear index λ. Population analyses accurately predicted the time-courses of Cp(S), NPT and INR. Multivariate analysis showed that CYP2C9*3 mutation and body surface area were predictors of CL(S), that VKORC1 and CYP4F2 polymorphisms were predictors of IC50, and that baseline NPT was a predictor of λ. CL(S) and λ were significantly lower in patients with INR≥4 than in those with INR<4 (190 mL/h vs 265 mL/h, P<0.01 and 3.2 vs 3.7, P<0.01, respectively). Finally, logistic regression analysis revealed that CL(S), ALT and hypertension contributed significantly to INR≥4. All these results indicate that factors associated with the reduced metabolic activity of warfarin represented by CL(S), might be critical determinants of the over-anticoagulation response during warfarin initiation in Asians.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT02065388.
authors.affiliation: Department of Biopharmaceutics, Meiji Pharmaceutical University, Tokyo, Japan.
authors.forename: Minami
authors.initials: M
authors.lastname: Ohara
authors.affiliation: Department of Biopharmaceutics, Meiji Pharmaceutical University, Tokyo, Japan.
authors.forename: Harumi
authors.initials: H
authors.lastname: Takahashi
authors.affiliation: Laboratory for International Alliance on Genomic Research, RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan; Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
authors.forename: Ming Ta Michael
authors.initials: MT
authors.lastname: Lee
authors.affiliation: Departments of Medicine and Neurology, Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Taoyuan, Taiwan.
authors.forename: Ming-Shien
authors.initials: MS
authors.lastname: Wen
authors.affiliation: Departments of Medicine and Neurology, Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Taoyuan, Taiwan.
authors.forename: Tsong-Hai
authors.initials: TH
authors.lastname: Lee
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
authors.forename: Hui-Ping
authors.initials: HP
authors.lastname: Chuang
authors.affiliation: Department of Biopharmaceutics, Meiji Pharmaceutical University, Tokyo, Japan.
authors.forename: Chen-Hui
authors.initials: CH
authors.lastname: Luo
authors.affiliation: Department of Biopharmaceutics, Meiji Pharmaceutical University, Tokyo, Japan.
authors.forename: Aki
authors.initials: A
authors.lastname: Arima
authors.affiliation: Department of Biopharmaceutics, Meiji Pharmaceutical University, Tokyo, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Onozuka
authors.affiliation: Department of Biopharmaceutics, Meiji Pharmaceutical University, Tokyo, Japan.
authors.forename: Rui
authors.initials: R
authors.lastname: Nagai
authors.affiliation: Department of Biopharmaceutics, Meiji Pharmaceutical University, Tokyo, Japan.
authors.forename: Mari
authors.initials: M
authors.lastname: Shiomi
authors.affiliation: Faculty of Pharmacy, Center for Clinical Pharmacy, Musashino University, Tokyo, Japan.
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Mihara
authors.affiliation: School of Medicine, Juntendo University, Tokyo, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Morita
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
authors.forename: Yuan-Tsong
authors.initials: YT
authors.lastname: Chen
mesh_terms: D000368:Aged; D000925:Anticoagulants / Q000493:pharmacokinetics / Q000627:therapeutic use*; D044466:Asian People; D065729:Cytochrome P-450 CYP2C9 / Q000235:genetics*; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D000072470:Cytochrome P450 Family 4; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011110:Polymorphism, Genetic; D016896:Treatment Outcome; D064417:Vitamin K Epoxide Reductases / Q000235:genetics*; D014859:Warfarin / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use*
chemical_list: D000925:Anticoagulants; D014859:Warfarin; D003577:Cytochrome P-450 Enzyme System; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D000072470:Cytochrome P450 Family 4; C117480:CYP4F2 protein, human; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases