INTRODUCTION: Anticoagulants of the coumarin type are effective drugs for the treatment and prevention of thromboembolic diseases. However, they have a narrow therapeutic range and show inter- and intra-individual variability in dose requirement, largely conditioned by both environmental and genetic factors. METHODS: This prospective study investigated, during the initial phase of acenocoumarol therapy, the effect of CYP2C9 variant alleles and VKORC1 haplotypes, single and in combination, in 220 Italians. RESULTS: CYP2C9*3 was associated with a 25% dose reduction and an increased risk of over-anticoagulation (International Normalized Ratio [INR] > 6) on day 4. Two copies of the VKORC1*2 haplotype were associated with a 45% dose reduction and an increased risk of over-anticoagulation. Homozygosity for VKORC1*3 and VKORC1*4 was associated with an increased dose requirement and a reduced risk of over-anticoagulation. The VKORC1*3 or *4 plus CYP2C9*1 genotype combination was associated with the highest dose requirement and the lowest INR on day 4; VKORC1*2 plus CYP2C9*3 was associated with the lowest dose requirement, the highest INR and an increased risk of over-anticoagulation. Even though they spent approximately 50% of the time within the target therapeutic range, VKORC1*3 or *4 plus CYP2C9*1 carriers spent a large percentage of the remaining time below and carriers of VKORC1*2 plus CYP2C9*3 above the target range. DISCUSSION: The determination of VKORC1*3 and VKORC1*4 haplotypes may be an important addition to CYP2C9 and VKORC1*2 genotyping to identify patients at risk of being outside the target range during initial anticoagulation with acenocoumarol
Effects of CYP2C9 and VKORC1 on INR variations and dose requirements during initial phase of anticoagulant therapy / M. Spreafico, C. Lodigiani, Y. van Leeuven, D. Pizzotti, L.L. Rota, F. Rosendaal, P.M. Mannucci, F. Peyvandi. - In: PHARMACOGENOMICS. - ISSN 1462-2416. - 9:9(2008 Sep), pp. 1237-1250.
Effects of CYP2C9 and VKORC1 on INR variations and dose requirements during initial phase of anticoagulant therapy
M. SpreaficoPrimo
;P.M. MannucciPenultimo
;F. PeyvandiUltimo
2008
Abstract
INTRODUCTION: Anticoagulants of the coumarin type are effective drugs for the treatment and prevention of thromboembolic diseases. However, they have a narrow therapeutic range and show inter- and intra-individual variability in dose requirement, largely conditioned by both environmental and genetic factors. METHODS: This prospective study investigated, during the initial phase of acenocoumarol therapy, the effect of CYP2C9 variant alleles and VKORC1 haplotypes, single and in combination, in 220 Italians. RESULTS: CYP2C9*3 was associated with a 25% dose reduction and an increased risk of over-anticoagulation (International Normalized Ratio [INR] > 6) on day 4. Two copies of the VKORC1*2 haplotype were associated with a 45% dose reduction and an increased risk of over-anticoagulation. Homozygosity for VKORC1*3 and VKORC1*4 was associated with an increased dose requirement and a reduced risk of over-anticoagulation. The VKORC1*3 or *4 plus CYP2C9*1 genotype combination was associated with the highest dose requirement and the lowest INR on day 4; VKORC1*2 plus CYP2C9*3 was associated with the lowest dose requirement, the highest INR and an increased risk of over-anticoagulation. Even though they spent approximately 50% of the time within the target therapeutic range, VKORC1*3 or *4 plus CYP2C9*1 carriers spent a large percentage of the remaining time below and carriers of VKORC1*2 plus CYP2C9*3 above the target range. DISCUSSION: The determination of VKORC1*3 and VKORC1*4 haplotypes may be an important addition to CYP2C9 and VKORC1*2 genotyping to identify patients at risk of being outside the target range during initial anticoagulation with acenocoumarolFile | Dimensione | Formato | |
---|---|---|---|
14622416.9.9.1237[1].pdf
accesso riservato
Tipologia:
Publisher's version/PDF
Dimensione
699.71 kB
Formato
Adobe PDF
|
699.71 kB | Adobe PDF | Visualizza/Apri Richiedi una copia |
Pubblicazioni consigliate
I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.