药物基因组学方程对中国患者低强度华法林抗凝治疗剂量的预测效果分析

目的在接受低强度华法林抗凝治疗的中国患者人群中，验证华法林药物基因组学剂量预测方程的效果。方法在接受低强度华法林抗凝治疗（目标国际标准化比值INR为1．6至2．5）的226例中国患者人群中，分别比较已公开发表并符合本研究入选标准的药物基因组学方程的效果。效果评估指标包括剂量预测值位于实际值20％界限内的患者比例（20％界限内的患者比例）以及剂量预测值与实际值之间绝对误差的平均值（MAE）。结果8个入选的药物基因组学方程的平均MAE为（0．87±0．17）mg／d（0．73-1．17）mg／d]，平均20％界限内的患者比例为（43．8％±8．1％）（29．1％-52．1％）。配对比较显示，来自亚洲人群的方程的预测效果明显优于来自高加索人群的方程（OR：1．61-3．36，P≤0．02）；加入INR值或CYP4F2＊3的方程较未加入的方程预测效果更好加入INR的OR：1．71（1．08-2．72），P=0．029；加入CYP4F2＊3的OR：2．67（1．41-5．05），P=0．004]。结论来自亚洲人群，或者整合3个基因变异型和INR反应性的药物基因组学方程能更好地预测接受低强度抗凝治疗的中国患者人群的华法林剂量。

Performance of pharmacogenetic algorithms in dose prediction in Chinese patients under low intensity warfarin anticoagulation

Objective To validate the performance of multiple warfarin pharmacogenetic algorithms in Chinese patients under low intensity warfarin anticoagulation. Methods We sought to compare the performances of 8 eligible pharmacogenetic algorithms in a cohort of Chinese patients （n = 282） under low intensity warfarin anticoagulation with target international normalized ratio （INR） ranged from 1.6 to 2.5. The performance of each algorithm was evaluated by calculating the percentage of patients whose predicted dose fell within 20% of their actual therapeutic dose （percentage within 20%）, and the mean absolute error （MAE） between each predicted dose and actual stable dose. Results In the entire cohort, the pharmacogenetic algorithms could predict warfarin dose with the average MAE of （0.87 ＋ 0.17） mg/d （0.73-1.17 mg/d）, and the average percentage within 20% of （43.8% - 8.1%） （29.1%-52.1%）. By pairwise comparison, warfarin dose prediction was significantly more accurate with the algorithms derived from Asian patients （48.6%-50.0%） than those from Caucasian patients （29.1%-39.7%; OR： 1.61-3.36, P≤ 0.02）. Algorithms with additional covariates of INR values or CYP4F2＊3 performed better than those without the covariates （adding INR： OR =1.71 （1.08-2.72）, P ： 0.029; adding CYP4F2＊3： OR=2.67（1.41-5.05）, P=0.004）. Conclusions Algorithms derived from Asian patients （48.6%- 50.0%） can predict more accurately than those from Caucasian patients in the Chinese patients. Construction of a refinement pharmacogenetic algorithm integrating 3 genotypes （CYP2C9, VKORC1 and CYP4F2） and INR data should be warranted to improve the warfarin dose prediction in such patients.