Abstract
Background: Coumarin derivatives are effective medications for the treatment and prevention of thromboembolic events. However, they have a small therapeutic window and there is a large variability in anticoagulant response. Single nucleotide polymorphisms in CYP2C9 and VKORC1 explain approximately 40% of the coumarin dose variation. Objectives: To investigate the effects of two polymorphisms in CYP3A4 and one polymorphism in CYP4F2 on the stable phenprocoumon and acenocoumarol maintenance dose. Methods: The Pre-EU-PACT cohort (551 phenprocoumon and 372 acenocoumarol users) was used to investigate the effect of CYP3A4∗1B, CYP3A4∗22 and CYP4F2 V433M genotypes on the acenocoumarol and phenprocoumon maintenance dose. Unadjusted and adjusted mean coumarin maintenance dose differences were calculated and compared for each genotype using linear regression. The Committee Medical Ethics Leiden approved the study protocol and procedures were in accordance with the Helsinki Declaration. Results: For phenprocoumon, a significant increase in the maintenance dose of 0.13 mg/day was found for patients carrying one variant CYP4F2 allele (n = 185) if compared to wild type patients (2.17 mg/day, n = 325), and an even larger increase was found for patients carrying two CYP4F2 variant alleles (n = 41): plus 0.24 mg/day, trend-test p = 0.003. For CYP3A4∗22, a marginally significant effect (p = 0.05) was found on the phenprocoumon dose: mean dose for wild type patients was 2.25 mg/day (n = 496) and for patients carrying 1 variant allele -0.18 mg/day (n = 54), while no significant effect of CYP3A4∗1B variant alleles was found. For acenocoumarol, no significant effects on the maintenance dose were found for both CYP4F2 and CYP3A4 variant alleles, although the trend for CYP4F2 was comparable to the significant trend observed for phenprocoumon. Conclusions: Genetic variations in CYP4F2 appear to marginally increase the stable phenprocoumon maintenance dose. The same trend, although not significant, was found for acenocoumarol. No statistically significant effect was observed for CYP3A4 genotypes for both phenprocoumon and acenocoumarol.
Original language | English |
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Pages (from-to) | 327 |
Number of pages | 1 |
Journal | Pharmacoepidemiology and Drug Safety |
Volume | 22 |
DOIs | |
Publication status | Published - 1 Oct 2013 |
Keywords
- phenprocoumon
- acenocoumarol
- coumarin
- anticoagulant agent
- coumarin derivative
- maintenance drug dose
- pharmacoepidemiology
- risk management
- allele
- human
- patient
- genotype
- medical ethics
- wild type
- thromboembolism
- procedures
- linear regression analysis
- prevention
- single nucleotide polymorphism
- genetic variability
- drug therapy