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Genotypes Associated With Reduced Activity of VKORC1 and CYP2C9 and Their Modification of Acenocoumarol Anticoagulation During the Initial Treatment Period
Author(s) -
Teichert M,
Schaik RHN,
Hofman A,
Uitterlinden AG,
Smet PAGM,
Stricker BHCh,
Visser LE
Publication year - 2009
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1038/clpt.2008.294
Subject(s) - acenocoumarol , vkorc1 , cyp2c9 , vitamin k epoxide reductase , medicine , pharmacology , genotype , allele , regimen , warfarin , gastroenterology , biology , cytochrome p450 , genetics , gene , atrial fibrillation , metabolism
The objective of this study was to investigate the influence of genotypes associated with reduced activity of vitamin K epoxide reductase complex subunit 1 ( VKORC1 ) and cytochrome P450 2C9 ( CYP2C9 ) on anticoagulation with acenocoumarol during the first 6 weeks of treatment. In 1,525 patients from the Rotterdam Study who were started on anticoagulation therapy with acenocoumarol, the presence of VKORC1 1173C>T and CYP2C9 *2 and *3 allele variants was determined. The first international normalized ratio (INR) after initial standard dose, risk of overanticoagulation, and mean dosage at the end of the initiation period were compared between genotypes. The initial standard dosage significantly increased the risk of severe overanticoagulation by 85% for each additional VKORC1 T‐allele present. At the end of the initiation period, each VKORC1 T‐allele present was shown to decrease the required acenocoumarol dosage by 5.1 mg/week, while each CYP2C9 variant allele present reduced the required dosage by 1.8 mg/week. Our conclusion was that an initial standard dosing regimen with acenocoumarol increases the risk of severe overanticoagulation in patients with variant alleles of the VKORC1 and CYP2C9 genes. Clinical Pharmacology & Therapeutics (2009); 85 , 4, 379–386 doi: 10.1038/clpt.2008.294