title: Assessing the relative potency of (S)- and (R)-warfarin with a new PK-PD model, in relation to VKORC1 genotypes.
abstract: OBJECTIVE
  The purpose of this study is to develop a new pharmacokinetic-pharmacodynamic (PK-PD) model to characterise the contribution of (S)- and (R)-warfarin to the anticoagulant effect on patients in treatment with rac-warfarin.
  
  
  METHODS
  Fifty-seven patients starting warfarin (W) therapy were studied, from the first dose and during chronic treatment at INR stabilization. Plasma concentrations of (S)- and (R)-W and INRs were measured 12, 36 and 60 h after the first dose and at steady state 12-14 h after dosing. Patients were also genotyped for the G>A VKORC1 polymorphism. The PK-PD model assumed a linear relationship between W enantiomer concentration and INR and included a scaling factor k to account for a different potency of (R)-W. Two parallel compartment chains with different transit times (MTT1and MTT2) were used to model the delay in the W effect. PD parameters were estimated with the maximum likelihood approach.
  
  
  RESULTS
  The model satisfactorily described the mean time-course of INR, both after the initial dose and during long-term treatment. (R)-W contributed to the rac-W anticoagulant effect with a potency of about 27% that of (S)-W. This effect was independent of VKORC1 genotype. As expected, the slope of the PK/PD linear correlation increased stepwise from GG to GA and from GA to AA VKORC1 genotype (0.71, 0.90 and 1.49, respectively).
  
  
  CONCLUSIONS
  Our PK-PD linear model can quantify the partial pharmacodynamic activity of (R)-W in patients contemporaneously exposed to therapeutic (S)-W plasma levels. This concept may be useful in improving the performance of future algorithms aiming at identifying the most appropriate W maintenance dose.
authors.affiliation: Computer-Aided Process Engineering Laboratory (CAPE-lab), Department of Industrial Engineering, University of Padova, Via Marzolo 9, 35131, Padua, Italy.
authors.forename: Myriam
authors.initials: M
authors.lastname: Ferrari
authors.affiliation: Department of Cardiological, Thoracic and Vascular Sciences, University of Padova Medical School, Via Giustiniani 2, 35128, Padua, Italy.
authors.forename: Vittorio
authors.initials: V
authors.lastname: Pengo
authors.affiliation: Computer-Aided Process Engineering Laboratory (CAPE-lab), Department of Industrial Engineering, University of Padova, Via Marzolo 9, 35131, Padua, Italy.
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Barolo
authors.affiliation: Computer-Aided Process Engineering Laboratory (CAPE-lab), Department of Industrial Engineering, University of Padova, Via Marzolo 9, 35131, Padua, Italy.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Bezzo
authors.affiliation: Department of Medicine (DIMED), University of Padova Medical School, Via Giustiniani 2, 35128, Padua, Italy. roberto.padrini@unipd.it.
authors.forename: Roberto
authors.identifier: http://orcid.org/0000-0001-9699-3673
authors.initials: R
authors.lastname: Padrini
mesh_terms: D000368:Aged; D000465:Algorithms; D000925:Anticoagulants / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology; D005260:Female; D005838:Genotype; D006801:Humans; D019934:International Normalized Ratio; D016013:Likelihood Functions; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D011110:Polymorphism, Genetic; D013237:Stereoisomerism; D013997:Time Factors; D064417:Vitamin K Epoxide Reductases / Q000235:genetics*; D014859:Warfarin / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000925:Anticoagulants; D014859:Warfarin; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases
keywords: (R)-warfarin; (S)-warfarin; Pharmacodymamics; Pharmacokinetics; VKORC1