title: Theory-based pharmacokinetics and pharmacodynamics of S- and R-warfarin and effects on international normalized ratio: influence of body size, composition and genotype in cardiac surgery patients.
abstract: The aims of this study are to apply a theory-based mechanistic model to describe the pharmacokinetics (PK) and pharmacodynamics (PD) of S- and R-warfarin.
  
  
  
  Clinical data were obtained from 264 patients. Total concentrations for S- and R-warfarin were measured by ultra-high performance liquid tandem mass spectrometry. Genotypes were measured using pyrosequencing. A sequential population PK parameter with data method was used to describe the international normalized ratio (INR) time course. Data were analyzed with NONMEM. Model evaluation was based on parameter plausibility and prediction-corrected visual predictive checks.
  
  
  
  Warfarin PK was described using a one-compartment model. CYP2C9 *1/*3 genotype had reduced clearance for S-warfarin, but increased clearance for R-warfarin. The in vitro parameters for the relationship between prothrombin complex activity (PCA) and INR were markedly different (A = 0.560, B = 0.386) from the theory-based values (A = 1, B = 0). There was a small difference between healthy subjects and patients. A sigmoid EmaxPD model inhibiting PCA synthesis as a function of S-warfarin concentration predicted INR. Small R-warfarin effects was described by competitive antagonism of S-warfarin inhibition. Patients with VKORC1 AA and CYP4F2 CC or CT genotypes had lower C50 for S-warfarin.
  
  
  
  A theory-based PKPD model describes warfarin concentrations and clinical response. Expected PK and PD genotype effects were confirmed. The role of predicted fat free mass with theory-based allometric scaling of PK parameters was identified. R-warfarin had a minor effect compared with S-warfarin on PCA synthesis. INR is predictable from 1/PCA in vivo.
authors.affiliation: Department of Clinical Pharmacology, the First Affiliated Hospital of Soochow University, Suzhou, 215006, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Xue
authors.affiliation: Department of Pharmacology and Clinical Pharmacology, University of Auckland, New Zealand.
authors.forename: Nick
authors.initials: N
authors.lastname: Holford
authors.affiliation: Department of Clinical Pharmacology, the First Affiliated Hospital of Soochow University, Suzhou, 215006, China.
authors.forename: Xiao-Liang
authors.initials: XL
authors.lastname: Ding
authors.affiliation: Department of Cardiovascular Surgery, the First Affiliated Hospital of Soochow University, Suzhou, 215006, China.
authors.forename: Zhen-Ya
authors.initials: ZY
authors.lastname: Shen
authors.affiliation: Department of Clinical Pharmacology, the First Affiliated Hospital of Soochow University, Suzhou, 215006, China.
authors.forename: Chen-Rong
authors.initials: CR
authors.lastname: Huang
authors.affiliation: Department of Clinical Pharmacology, the First Affiliated Hospital of Soochow University, Suzhou, 215006, China.
authors.forename: Hua
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Clinical Pharmacology, the First Affiliated Hospital of Soochow University, Suzhou, 215006, China.
authors.forename: Jing-Jing
authors.initials: JJ
authors.lastname: Zhang
authors.affiliation: College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, China.
authors.forename: Zhe-Ning
authors.initials: ZN
authors.lastname: Guo
authors.affiliation: Department of Clinical Pharmacology, the First Affiliated Hospital of Soochow University, Suzhou, 215006, China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Xie
authors.affiliation: Department of Clinical Pharmacology, the First Affiliated Hospital of Soochow University, Suzhou, 215006, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Department of Clinical Pharmacology, the First Affiliated Hospital of Soochow University, Suzhou, 215006, China.
authors.forename: Zhi-Yao
authors.initials: ZY
authors.lastname: Chen
authors.affiliation: Department of Clinical Pharmacology, the First Affiliated Hospital of Soochow University, Suzhou, 215006, China.
authors.forename: Lin-Sheng
authors.initials: LS
authors.lastname: Liu
authors.affiliation: Department of Clinical Pharmacology, the First Affiliated Hospital of Soochow University, Suzhou, 215006, China.|College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, China.
authors.forename: Li-Yan
authors.initials: LY
authors.lastname: Miao
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000925:Anticoagulants / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D001823:Body Composition / Q000502:physiology; D049628:Body Size / Q000502:physiology; D006348:Cardiac Surgical Procedures / Q000379:methods*; D002851:Chromatography, High Pressure Liquid; D000072470:Cytochrome P450 Family 4 / Q000235:genetics; D005260:Female; D005838:Genotype; D006801:Humans; D019934:International Normalized Ratio; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D017711:Nonlinear Dynamics; D013237:Stereoisomerism; D053719:Tandem Mass Spectrometry; D064417:Vitamin K Epoxide Reductases / Q000235:genetics; D014859:Warfarin / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D055815:Young Adult
chemical_list: D000925:Anticoagulants; D014859:Warfarin; D000072470:Cytochrome P450 Family 4; C117480:CYP4F2 protein, human; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases
keywords: body size; fat free mass; international normalized ratio; pharmacogenomics; turnover; warfarin