Optimization of warfarin dose by population-specific pharmacogenomic algorithm

Abstract

To optimize the warfarin dose, a population-specific pharmacogenomic algorithm was developed using multiple linear regression model with vitamin K intake and cytochrome P450 IIC polypeptide9 (CYP2C9(*)2 and (*)3), vitamin K epoxide reductase complex 1 (VKORC1(*)3, (*)4, D36Y and -1639 G>A) polymorphism profile of subjects who attained therapeutic international normalized ratio as predictors. New algorithm was validated by correlating with Wadelius, International Warfarin Pharmacogenetics Consortium and Gage algorithms; and with the therapeutic dose (r=0.64, P<0.0001). New algorithm was more accurate (Overall: 0.89 vs 0.51, warfarin resistant: 0.96 vs 0.77 and warfarin sensitive: 0.80 vs 0.24), more sensitive (0.87 vs 0.52) and specific (0.93 vs 0.50) compared with clinical data. It has significantly reduced the rate of overestimation (0.06 vs 0.50) and underestimation (0.13 vs 0.48). To conclude, this population-specific algorithm has greater clinical utility in optimizing the warfarin dose, thereby decreasing the adverse effects of suboptimal dose.

A new warfarin dosing algorithm including VKORC1 3730 G > A polymorphism: comparison with results obtained by other published algorithms

“…The more accurate identification of the high-dose group was probably due to incorporation of the VKORC1 polymorphism associated with warfarin resistance in the regression equation. Similar results were reported in a previously published study [13] in which an algorithm incorporating the VKORC1 3730 G > A was proposed in an Indian population. We could not evaluate this algorithm in our analysis because it also included the VKORC1 6009 C > T, which was not assessed in our patients.…”

“…These pharmacogenetic algorithms included different combinations of demographic and genotypic variables, mostly polymorphisms in CYP2C9 and VKORC1 genes associated with warfarin sensitivity. In fact, to our knowledge, only one algorithm including the VKORC1 3730 G > A SNP associated with warfarin resistance has been published so far, and it addressed an Indian population [13], which differs from the Italian population in gene pool, lifestyle risk factors, and demographic characteristics.…”

Prediction of Warfarin Dose: Why, When and How?

“…Most dark green vegetables such as broccoli, Brussels sprouts and spinach contain high levels of vitamin K (>100 µg/2 dl), but also other common foodstuffs contain a fairly large amount of vitamin K [17]. It is estimated that an increase in vitamin K intake of 100 µg per day for 4 consecutive days lowers the INR by 0.2 and vitamin K intake has therefore been incorporated into some warfarin dose prediction models [18,19].…”

Pharmacogenetic Aspects of Coumarinic Oral Anticoagulant Therapies

“…A recent study from southern India has been done by Pavani et al [36] to optimize the warfarin dose. Vitamin K uptake, CYP2C9*2, CYP2C9*3, VKORC1*3, VKORC1*4, D36Y and -1639 G [ A polymorphisms were used to develop a pharmacogenomic algorithm using multiple linear regression models.…”