Validation of pharmacogenetic algorithms and warfarin dosing table in Egyptian patients

Abstract

Background: Warfarin remains a difficult drug to use due to the large variability in dose response. Clear understanding of the accuracy of warfarin pharmacogenetic dosing methods might lead to appropriate control of anticoagulation.

Objective: This study aims to evaluate the accuracy of warfarin dosing table and two pharmacogenetic algorithms, namely the algorithms of Gage et al. (Clin Pharmacol Ther 84:326-331, 2008), and the International Warfarin Pharmacogenetics Consortium algorithm (IWPC) in a real Egyptian clinical setting. Additionally, three non-pharmacogenetic dosing methods (the Gage, IWPC clinical algorithms and the empiric 5 mg/day dosing) were evaluated.

Setting: Sixty-three Egyptian patients on a stable therapeutic warfarin dose were included. Patients were recruited from the outpatient clinic of the critical care medicine department.

Methods: CYP2C9 and VKORC1 polymorphisms were genotyped by real time PCR system. Predicted doses by all dosing methods were calculated and compared with the actual therapeutic warfarin doses.

Results: The Gage algorithm (adjusted R(2) = 0.421, and mean absolute error (MAE) = 3.3), and IWPC algorithm (adjusted R(2) = 0.419, MAE = 3.2) produced better accuracy than did the warfarin dosing table (adjusted R(2) = 0.246, MAE = 3.5), the two clinical algorithms (R(2) = 0.24, MAE = 3.7) and the fixed dose approach (MAE = 3.9). However, all dosing models produced comparable clinical accuracy with respect to proportion of patients within 1 mg/day of actual dose (ideal dose). Non-pharmacogenetic methods severely over-predicted dose (defined as ≥2 mg/day more than actual dose) compared to the three pharmacogenetic models. In comparison to non-pharmacogenetic methods, the three pharmacogenetic models performed better regarding the low dose group in terms of percentage of patients within ideal dose. In the high dose group, none of the dosing models predicted warfarin doses within ideal dose.

Conclusion: Our study showed that genotype-based dosing improved prediction of warfarin therapeutic dose beyond that available with the fixed-dose approach or the clinical algorithms, especially in the low-dose group. However, the two pharmacogenetic algorithms were the most accurate.