title: Validation of pharmacogenetic algorithms and warfarin dosing table in Egyptian patients.
abstract: BACKGROUND
  Warfarin remains a difficult drug to use due to the large variability in dose response. Clear understanding of the accuracy of warfarin pharmacogenetic dosing methods might lead to appropriate control of anticoagulation.
  
  
  OBJECTIVE
  This study aims to evaluate the accuracy of warfarin dosing table and two pharmacogenetic algorithms, namely the algorithms of Gage et al. (Clin Pharmacol Ther 84:326-331, 2008), and the International Warfarin Pharmacogenetics Consortium algorithm (IWPC) in a real Egyptian clinical setting. Additionally, three non-pharmacogenetic dosing methods (the Gage, IWPC clinical algorithms and the empiric 5 mg/day dosing) were evaluated.
  
  
  METHODS
  Sixty-three Egyptian patients on a stable therapeutic warfarin dose were included. Patients were recruited from the outpatient clinic of the critical care medicine department.
  
  
  METHODS
  CYP2C9 and VKORC1 polymorphisms were genotyped by real time PCR system. Predicted doses by all dosing methods were calculated and compared with the actual therapeutic warfarin doses.
  
  
  RESULTS
  The Gage algorithm (adjusted R(2) = 0.421, and mean absolute error (MAE) = 3.3), and IWPC algorithm (adjusted R(2) = 0.419, MAE = 3.2) produced better accuracy than did the warfarin dosing table (adjusted R(2) = 0.246, MAE = 3.5), the two clinical algorithms (R(2) = 0.24, MAE = 3.7) and the fixed dose approach (MAE = 3.9). However, all dosing models produced comparable clinical accuracy with respect to proportion of patients within 1 mg/day of actual dose (ideal dose). Non-pharmacogenetic methods severely over-predicted dose (defined as ≥2 mg/day more than actual dose) compared to the three pharmacogenetic models. In comparison to non-pharmacogenetic methods, the three pharmacogenetic models performed better regarding the low dose group in terms of percentage of patients within ideal dose. In the high dose group, none of the dosing models predicted warfarin doses within ideal dose.
  
  
  CONCLUSIONS
  Our study showed that genotype-based dosing improved prediction of warfarin therapeutic dose beyond that available with the fixed-dose approach or the clinical algorithms, especially in the low-dose group. However, the two pharmacogenetic algorithms were the most accurate.
authors.affiliation: Critical Care Medicine Department, Cairo University Hospitals, Cairo, Egypt. naglaabazan@yahoo.com
authors.forename: Naglaa Samir
authors.initials: NS
authors.lastname: Bazan
authors.forename: Nirmeen Ahmed
authors.initials: NA
authors.lastname: Sabry
authors.forename: Amal
authors.initials: A
authors.lastname: Rizk
authors.forename: Sherif
authors.initials: S
authors.lastname: Mokhtar
authors.forename: Osama
authors.initials: O
authors.lastname: Badary
mesh_terms: D000293:Adolescent; D000328:Adult; D000465:Algorithms; D000925:Anticoagulants / Q000008:administration & dosage* / Q000009:adverse effects; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D001777:Blood Coagulation / Q000187:drug effects* / Q000235:genetics; D065729:Cytochrome P-450 CYP2C9; D004305:Dose-Response Relationship, Drug; D054796:Drug Dosage Calculations; D016903:Drug Monitoring / Q000379:methods; D004534:Egypt; D005260:Female; D005838:Genotype; D006801:Humans; D019934:International Normalized Ratio; D008297:Male; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000235:genetics*; D010597:Pharmacogenetics / Q000379:methods*; D010641:Phenotype; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D011237:Predictive Value of Tests; D015203:Reproducibility of Results; D064417:Vitamin K Epoxide Reductases; D014859:Warfarin / Q000008:administration & dosage* / Q000009:adverse effects; D055815:Young Adult
chemical_list: D000925:Anticoagulants; D014859:Warfarin; 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