title: Quantifying the effect of covariates on concentrations and effects of steady-state phenprocoumon using a population pharmacokinetic/pharmacodynamic model.
abstract: OBJECTIVE
  The oral anticoagulant phenprocoumon, similar to other vitamin K antagonists, is characterized by pronounced interindividual variability in the doses needed to achieve the desired therapeutic effect. Previous studies assessed the effect of genetic and demographic covariates on empirical dose requirements of phenprocoumon to enable individualized dose prediction. The aim of the present study was to quantify major sources of interindividual variability separately on the pharmacokinetics and pharmacodynamics of phenprocoumon using a population pharmacokinetic-pharmacodynamic model.
  
  
  METHODS
  A single steady-state blood sample was collected from 278 patients and assayed by liquid chromatography-tandem mass spectrometry for phenprocoumon and its metabolites. Genotyping was performed for variants of the cytochrome P450 (CYP) 2C9 (CYP2C9) and vitamin K epoxide reductase complex, subunit 1 (VKORC1) genes. Effects were quantified by international normalized ratio (INR). Data were analyzed simultaneously using NONMEM VII.
  
  
  RESULTS
  The model confirmed CYP2C9 and VKORC1 variants as the major predictors of variability in phenprocoumon concentrations and effects, together with body weight, age, comedication with CYP3A modifiers (i.e. inhibitors or inducers) and presence of atrial fibrillation. These covariates explained 50.0 % of the observed variability in the model parameters. Phenprocoumon clearance fractions mediated per CYP2C9 allele were 13.4, 9.5 and 5.7 mL/h for the 1, 2 and 3 variants, respectively. An additional clearance fraction of 5.3 mL/h was independent of CYP2C9 activity. Homozygous VKORC1 wild-type carriers were estimated to have a 2.13-fold higher phenprocoumon exposure requirement than homozygous 1173 C>T carriers to achieve the same effect on INR.
  
  
  CONCLUSIONS
  The model provides a deeper insight in the separate pharmacokinetic and pharmacodynamic parts of phenprocoumon action. Thus, it provides important information for individualized dose prediction, with the option to include further covariates not studied here with known effects on individual pharmacokinetic or pharmacodynamic processes.
authors.affiliation: Department of Pharmacology, Clinical Pharmacology Unit, University Hospital, University of Cologne, Gleueler Straße 24, 50931 Cologne, Germany.
authors.forename: Khaled
authors.initials: K
authors.lastname: Abduljalil
authors.forename: Simone
authors.initials: S
authors.lastname: Lazar
authors.forename: Michael
authors.initials: M
authors.lastname: Natanzon
authors.forename: Weidong
authors.initials: W
authors.lastname: Wu
authors.forename: Gregor
authors.initials: G
authors.lastname: Zadoyan
authors.forename: Benedict
authors.initials: B
authors.lastname: Steffens
authors.forename: Victoria
authors.initials: V
authors.lastname: Kohl
authors.forename: Klaus
authors.initials: K
authors.lastname: Mörike
authors.forename: Dorota
authors.initials: D
authors.lastname: Tomalik-Scharte
authors.forename: Julia
authors.initials: J
authors.lastname: Stingl
authors.forename: Matthias
authors.initials: M
authors.lastname: Schwab
authors.forename: Job
authors.initials: J
authors.lastname: Harenberg
authors.forename: Christoph
authors.initials: C
authors.lastname: Gleiter
authors.forename: Uwe
authors.initials: U
authors.lastname: Fuhr
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000925:Anticoagulants / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics; D001281:Atrial Fibrillation / Q000503:physiopathology; D002853:Chromatography, Liquid; D003430:Cross-Sectional Studies; D065729:Cytochrome P-450 CYP2C9; D004305:Dose-Response Relationship, Drug; D005260:Female; D005838:Genotype; D006801:Humans; D019934:International Normalized Ratio; D008297:Male; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000235:genetics; D008954:Models, Biological; D017711:Nonlinear Dynamics; D010644:Phenprocoumon / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D053719:Tandem Mass Spectrometry; D064417:Vitamin K Epoxide Reductases
chemical_list: D000925:Anticoagulants; D006899:Mixed Function Oxygenases; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases; D010644:Phenprocoumon