VKORC1 and CYP2C9 Genotypes and Phenprocoumon Anticoagulation Status: Interaction Between both Genotypes Affects Dose Requirement

• Published in: Clinical pharmacology and therapeutics Vol. 81; no. 2; pp. 185 - 193
• Main Authors: Schalekamp, T, Brassé, B P, Roijers, J F M, Meegen, E, Meer, F J M, Wijk, E M, Egberts, A C G, Boer, A
• Format: Journal Article
• Language: English
• Published: New York, NY Nature Publishing 01-02-2007
• Subjects: Aged; Alleles; Anticoagulants - administration & dosage; Anticoagulants - pharmacokinetics; Anticoagulants - therapeutic use; Aryl Hydrocarbon Hydroxylases - genetics; Biological and medical sciences; Chi-Square Distribution; Cytochrome P-450 CYP2C9; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Gene Frequency; Genotype; Humans; Kaplan-Meier Estimate; Linkage Disequilibrium; Male; Medical sciences; Middle Aged; Mixed Function Oxygenases - genetics; Pharmacology. Drug treatments; Phenprocoumon - administration & dosage; Phenprocoumon - pharmacokinetics; Phenprocoumon - therapeutic use; Polymorphism, Genetic; Prospective Studies; Time Factors; Treatment Outcome; Vitamin K Epoxide Reductases; Human; Typing; Enzyme; Isozyme; Cytochrome P450; Interaction; VKORC1 gene; Genotype; Anticoagulant; Antivitamin K; Treatment; Vitamin-K-epoxide reductase (warfarin-sensitive); Oxidoreductases; Phenprocoumon; Dose; CYP2C9 gene
• ISSN: 0009-9236; 1532-6535
• DOI: 10.1038/sj.clpt.6100036

In a prospective follow‐up study of the effects of VKORC1 and CYP2C9 genotypes on the anticoagulation status of patients, we assessed the CYP2C9 and the VKORC1 C1173T genotypes of patients during the initial 6 months of phenprocoumon treatment. We used linear regression models and Cox proportional hazard models to determine the effects of the VKORC1 and CYP2C9 genotypes on phenprocoumon dose requirements, overanticoagulation, and time to achieve stability. Allele frequencies of interest within the cohort (N=281) were 40.8% VKORC1 T‐1173, 12.8% CYP2C9*2, and 6.9% CYP2C9*3. In patients with the VKORC1 CC genotype, carriers of a CYP2C9 polymorphism needed dosages that were nearly 30% lower than those for CYP2C9*1/*1 patients (P<0.001). In patients with a VKORC1 polymorphism, differences between carriers of a CYP2C9 polymorphism and CYP2C9*1/*1 were far smaller and largely not statistically significant. A larger part of the variability in dose requirement was explained by the VKORC1 genotype than by the CYP2C9 genotype (28.7% and 7.2%, respectively). Carriers of a combination of a CYP2C9 polymorphism and a VKORC1 polymorphism had a strongly increased risk of severe overanticoagulation (hazard ratio (HR) 7.20, P=0.002). Only carriers of a CYP2C9*2 allele had a decreased chance to achieve stability compared to CYP2C9*1/*1 patients (HR 0.61, P=0.004). In conclusion, the VKORC1 genotype modifies the effect of the CYP2C9 genotype on phenprocoumon dose requirements. A combination of polymorphisms of both genotypes is associated with a strongly increased risk of overanticoagulation, whereas delayed stabilization is mainly associated with the CYP2C9 genotype.
Clinical Pharmacology & Therapeutics (2007) 81, 185–193. doi:10.1038/sj.clpt.6100036; published online 27 December 2006