Establishment of acenocoumarol pharmacogenetic algorithm including CYP2C9 and VKORC1 genotypes in Bulgarian patients treated with coumarin anticoagulants
DOI:
https://doi.org/10.2478/AMB-2025-0039Keywords:
acenocoumarol, CYP2C9, VKORC1, algorithmAbstract
Introduction: Acenocoumarol, a 4-hydroxycoumarin derivative, is widely prescribed for the primary and secondary prevention of thromboembolic disorders. Maintenance dosing of acenocoumarol is significantly influenced by polymorphic variants in the CYP2C9 and VKORC1 genes. Other critical factors affecting dosing include patient age, diet, body height and weight, and potential drug interactions, particularly with concurrent use of medications such as amiodarone and statins. Objectives: The primary goal of this investigation is to develop a pharmacogenetic dosing algorithm for acenocoumarol based on CYP2C9 and VKORC1 genotypes in Bulgarian patients. Methods: A total of 120 patients, aged 18 to 70 years, undergoing stable acenocoumarol therapy, were enrolled in this study. DNA was extracted using the Chemagic Magnetic Separation Module I (Chemagen AG) following the manufacturer’s protocol, at the Molecular Medicine Center, Medical University – Sofia, Bulgaria. To develop the final clinical and pharmacogenetic dosing algorithms, variables such as age, gender, diagnosis, weight, amiodarone use, and genotypes (CYP2C9*2, CYP2C9*3, and VKORC1-1639G>A) were incorporated into a multiple linear regression (MLR) model. Results: For the analysis, we conducted genotyping of ten polymorphic variants across four genes relevant to acenocoumarol response: CYP2C9*2 (rs1799853), CYP2C9*3 (rs1057310), VKORC1*2A (rs9923231 and rs9934438), VKORC1*2B (rs2884737), VKORC1*3 (rs7294), VKORC1*4 (rs17708472), and APOE (rs7412 and rs429358). Single-component and multiple linear regression analyses were applied to evaluate both genetic and non-genetic factors and their effects on the daily acenocoumarol dose in the patient cohort. The resulting mathematical dosing algorithm is provided below: Optimal daily maintenance dose of acenocoumarol = 5.939 – 0.033*(age in years) – 1.149* (number of VKORC1*2A alleles) + 0.433*(number of VKORC1*3 alleles) – 1.425*(number of CYP2C9*2 alleles) – 0.486*(number of CYP2C9*3 alleles). Conclusion: The multivariate analysis revealed that age and the presence of CYP2C9*2, CYP2C9*3, VKORC1*2A, and VKORC1*3 alleles accounted for 43.8% of the variation in the average daily maintenance dose of acenocoumarol.
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Copyright (c) 2025 R. Tzveova, R. Saraeva, A. Dimitrova-Karamfilova, G. Nachev, V. Mitev, R. Kaneva, D. Pendicheva-Duhlenska (Author)
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Journal Acta Medica Bulgarica 
