title: Creating a genotype-based dosing algorithm for acenocoumarol steady dose.
abstract: Acenocoumarol is a commonly prescribed anticoagulant drug for the prophylaxis and treatment of venous and arterial thromboembolic disorders in several countries. In counterpart of warfarin, there is scarce information about pharmacogenetic algorithms for steady acenocoumarol dose estimation. The aim of this study was to develop an algorithm of prediction for acenocoumarol.The algorithm was created using the data from 973 retrospectively selected anticoagulated patients and was validated in a second independent cohort adding up to 2,683 patients. The best regression model to predict stable dosage in the Primary Cohort included clinical factors (age and body mass index, BSA) and genetic variants (VKORC1, CYP2C9*  and  CYP4F2  polymorphisms) and explained up to 50% of stable dose. In the validation study the clinical algorithm yielded an adjusted R²=0.15 (estimation´s standard error=4.5) and the genetic approach improved the dose forecast up to 30% (estimation´s standard error=4.6). Again, the best model combined clinical and genetic factors (R² = 0.48; estimation´s standard error=4) which provided the best results of doses estimates within 20% of the real dose in patients taking lower (≤ 7 mg/week) or higher (≥ 25 mg/week) acenocoumarol doses. In conclusion, we developed a prediction algorithm using clinical data and three polymorphisms in  VKORC1, CYP2C9*  and  CYP4F2  genes that provided a steady acenocoumarol dose for about 50% of patients in the Validation Cohort. Such algorithm was especially useful to patients who need higher or lower acenocoumarol doses, those patients with higher time required until their stabilisation and are more prone to suffer a treatment derived complication.
authors.affiliation: Hospital Universitario Morales Meseguer, Centro Regional de Hemodonación, University of Murcia, Avda. De los Vélez s/n, 30008 Murcia, Spain.
authors.forename: Juan J
authors.initials: JJ
authors.lastname: Cerezo-Manchado
authors.forename: Mario
authors.initials: M
authors.lastname: Rosafalco
authors.forename: Ana I
authors.initials: AI
authors.lastname: Antón
authors.forename: Virginia
authors.initials: V
authors.lastname: Pérez-Andreu
authors.forename: Nuria
authors.initials: N
authors.lastname: Garcia-Barberá
authors.forename: Ana B
authors.initials: AB
authors.lastname: Martinez
authors.forename: Javier
authors.initials: J
authors.lastname: Corral
authors.forename: Vincente
authors.initials: V
authors.lastname: Vicente
authors.forename: Rocio
authors.initials: R
authors.lastname: González-Conejero
authors.forename: Vanessa
authors.initials: V
authors.lastname: Roldán
mesh_terms: D000074:Acenocoumarol / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000465:Algorithms; D000925:Anticoagulants / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics / Q000378:metabolism; D001777:Blood Coagulation / Q000187:drug effects*; D001830:Body Surface Area; D016009:Chi-Square Distribution; D065729:Cytochrome P-450 CYP2C9; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D000072470:Cytochrome P450 Family 4; D054796:Drug Dosage Calculations; D016903:Drug Monitoring; D005260:Female; D005343:Fibrinolytic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D016018:Least-Squares Analysis; D016014:Linear Models; D008297:Male; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000235:genetics / Q000378:metabolism; D015999:Multivariate Analysis; D010597:Pharmacogenetics; D010641:Phenotype; D011110:Polymorphism, Genetic; D015203:Reproducibility of Results; D012189:Retrospective Studies; D064417:Vitamin K Epoxide Reductases
chemical_list: D000925:Anticoagulants; D005343:Fibrinolytic Agents; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; D000072470:Cytochrome P450 Family 4; C117480:CYP4F2 protein, human; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases; D000074:Acenocoumarol