Study based on genotype and real warfarin dosage: suitable warfarin formula for Chinese population_Chinese Journal of Evidence-Based Medicine

Authors：

XIE Jing ^1,2 , HU Xin ¹ ,  YANG Liping ¹

1. Department of Pharmacy, Beijing Hospital, Ministry of Public Health, Assessment of Clinical Drugs Risk and Individual Application Key Laboratory, Beijing, 100730, P.R.China;
2. Department of Pharmacy, Beijing Youan Hospital of Capital Medical University, Beijing, 100069, P.R.China;

Corresponding author：

YANG Liping, Email: yanglp_2000@hotmail.com

Keywords：

Warfarin; Genotype; Dose prediction formula; Maintenance dose; Chinese population

DOI：

10.7507/1672-2531.201706077

Video：

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Objectives To compare different formula calculated dosages with the actual doses of warfarin from patients in Beijing Hospital so as to investigate suitable warfarin dosing models for Chinese patients.Methods One hundred and three Chinese patients with long-term prescription of warfarin were randomly selected from Beijing Hospital from July 2012 to May 2013. The CYP2C9 and VKROC1 genotypes and basic statistical information were collected. SPSS 18.0 software was used to compare the differences between different formula calculated dosages and the actual dosages of warfarin.Results Five genotypes were found in 103 patients, including: CYP2C9 AA genotype + VKORC1 AA genotype (n=72, 69.9%), CYP2C9 AA genotype + VKORC1 AG genotype (n=17, 16.5%), CYP2C9 AC genotype + VKORC1 AA genotype (n=10, 9.7%), CYP2C9 AC genotype + VKORC1 AG genotype (n=3, 2.9%) and CYP2C9 AA genotype + VKORC1 GG genotype (n=1, 1%). Compared with the actual dosages of warfarin, the degree of coincidence was highest for dosages calculated by Jeffrey’s formula.Conclusions Using Jeffrey’s formula to calculate warfarin dosages may be more suitable for Chinese patients with using long-term warfarin. Due to limited sample size, prospective and large sample size studies are required to verify the above conclusion.

Citation： XIE Jing, HU Xin, YANG Liping. Study based on genotype and real warfarin dosage: suitable warfarin formula for Chinese population. Chinese Journal of Evidence-Based Medicine, 2019, 19(9): 1012-1017. doi: 10.7507/1672-2531.201706077 Copy

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2.	Liu N, Irvin MR, Zhi D, et al. Patient factors that influence warfarin dose response. Pharm Pract, 2010, 23(3): 194-204.
3.	Kaye JB, Schultz LE, Steiner HE, et al. Estimation of the warfarin dose with clinical and pharmacogenetic data. N Engl J Med, 2009, 360(8): 753-764.
4.	Anderson JL, Horne BD, Stevens SM, et al. Randomized trial of genotype-guided versus standard warfarin dosing in patients initiating oral anticoagulation. Circulation, 2007, 116(22): 2563-2570.
5.	Miao L, Yang J, Huang C. Contribution of age, body weight, and CYP2C9 and VKORC1 genotype to the anticoagulant response to warfarin: proposal for a new dosing regimen in Chinese patients. Eur J Clin Pharmacol, 2007, 63(12): 1135-1141.
6.	赵磊, 贾玫. CYP2C91075A>C和VKORC1-1639G>A基因多态性与华法林用药剂量差异的相关性及检测方法研究. 中华检验医学杂志, 2012, 35(11): 1010-1015.
7.	刘凡, 谢瑞芹, 杨晓红, 等. 河北省汉族人群CYP450+2C9和VKORC1基因多态性与华法林剂量相关性研究. 中华流行病学杂志, 2010, 31(2): 218-222.
8.	Ohno M, Yamamoto A, Ono A, et al. Influence of clinical and genetic factors on warfarin dose requirements among Japanese patients. Eur J Clin Pharmacol, 2009, 65(11): 1097-1103.
9.	郭伟, 王增智, 陈勇. VKORC1-1639G>A、CYP2C9*3基因多态性及年龄、体质量对汉族肺血栓栓塞症患者华法林稳定剂量的影响. 国际呼吸杂志, 2012, 32(21): 1621-1628.
10.	Schalekamp T, Brassé BP, Roijers JF, et al. VKORC1 and CYP2C9 genotypes and phenprocoumon anticoagulation status: interaction between both genotypes affects dose requirement. Clin Pharmacol Ther, 2007, 81(2): 185-193.
11.	Miyagata Y, Nakai K, Sugiyama Y. Clinical significance of combined CYP2C9 and VKORC1 genotypes in Japanese patients requiring warfarin. Int Heart J, 2011, 52(1): 44-49.
12.	Limdi NA, Wadelius M, Cavallari L, et al. Warfarin pharmacogenetics: a single VKORC1 polymorphism is predictive of dose across 3 racial groups. Blood, 2010, 115(18): 3827-3834.
13.	Geisen C, Watzka M, Sittinger K, et al. VKORC1 haplotypes and their impact on the inter-individual and inter-ethnical variability of oral anticoagulation. Thromb Haemost, 2005, 94(4): 773-779.
14.	Kosaki K, Yamaghishi C, Sato R, et al. 1173C>T polymorphism in VKORC1 modulates the required warfarin dose. Pediatr Cardiol, 2006, 27(6): 685-688.
15.	Yang J, Huang C, Shen Z, et al. Contribution of 1173C > T polymorphism in the VKORC1 gene to warfarin dose requirements in Han Chinese patients receiving anticoagulation. Int J Clin Pharmacol Ther, 2011, 49(1): 23-29.
16.	Patillon B, Luisi P, Blanché H, et al. Positive selection in the chromosome 16 VKORC1 genomic region has contributed to the variability of anticoagulant response in humans. PLoS One, 2012, 7(12): 53049.
17.	Limdi NA, Wadelius M, Cavallari L, et al. Warfarin pharmacogenetics: a single VKORC1 polymorphism is predictive of dose across 3 racial groups. Thromb Haemost, 2010, 115(18): 3827-3834.
18.	Daneshjou R, Tatonetti NP, Karczewski KJ, et al. Pathway analysis of genome-wide data improves warfarin dose prediction. BMC Genomics, 2013, 14(Suppl 3): S11.
19.	Huang SW, Chen HS, Wang XQ, et al. Validation of VKORC1 and CYP2C9 genotypes on interindividual warfarin maintenance dose: a prospective study in Chinese patients. Pharmacogenet Genomics, 2009, 19(3): 226-234.
20.	Zhong SL, Yu XY, Liu Y, et al. Integrating interacting drugs and genetic variations to improve the predictability of warfarin maintenance dose in Chinese patients. Pharmacogenet Genomics, 2012, 22(3): 176-282.
21.	杨晶晶, 于锋, 葛卫红, 等. 华法林个体化剂量调整模型的建立和应用. 药学与临床研究, 2010, 18(3): 269-273.
22.	Mushiroda T, Ohnishi Y, Saito S, et al. Association of VKORC1 and CYP2C9 polymorphisms with warfarin dose requirements in Japanese patients. Hum Genet, 2006, 51(3): 249-253.
23.	Gan GG, Phipps ME, Lee MM, et al. Contribution of VKORC1 and CYP2C9 polymorphisms in the interethnic variability of warfarin dose in Malaysian populations. Ann Hematol, 2011, 90(6): 635-641.
24.	Sangviroon A, Panomvana D, Tassaneeyakul W, et al. Pharmacokinetic and pharmacodynamic variation associated with VKORC1 and CYP2C9 polymorphisms in Thai patients taking warfarin. Drug Metab Pharmacokinet, 2010, 25(6): 531-538.
25.	Gaikwad T, Ghosh K, Shetty S. VKORC1 and CYP2C9 genotype distribution in Asian countries. Thromb Res, 2014, 134(3): 1-8.

1. Dharmarajan TS, Gupta A, Baig MA, et al. Warfarin: implementing its safe use in hospitalized patients from nursing homes and community through a performance improvement initiative. Am Med Dir Assoc, 2011, 12(7): 518-523.
2. Liu N, Irvin MR, Zhi D, et al. Patient factors that influence warfarin dose response. Pharm Pract, 2010, 23(3): 194-204.
3. Kaye JB, Schultz LE, Steiner HE, et al. Estimation of the warfarin dose with clinical and pharmacogenetic data. N Engl J Med, 2009, 360(8): 753-764.
4. Anderson JL, Horne BD, Stevens SM, et al. Randomized trial of genotype-guided versus standard warfarin dosing in patients initiating oral anticoagulation. Circulation, 2007, 116(22): 2563-2570.
5. Miao L, Yang J, Huang C. Contribution of age, body weight, and CYP2C9 and VKORC1 genotype to the anticoagulant response to warfarin: proposal for a new dosing regimen in Chinese patients. Eur J Clin Pharmacol, 2007, 63(12): 1135-1141.
6. 赵磊, 贾玫. CYP2C91075A>C和VKORC1-1639G>A基因多态性与华法林用药剂量差异的相关性及检测方法研究. 中华检验医学杂志, 2012, 35(11): 1010-1015.
7. 刘凡, 谢瑞芹, 杨晓红, 等. 河北省汉族人群CYP450+2C9和VKORC1基因多态性与华法林剂量相关性研究. 中华流行病学杂志, 2010, 31(2): 218-222.
8. Ohno M, Yamamoto A, Ono A, et al. Influence of clinical and genetic factors on warfarin dose requirements among Japanese patients. Eur J Clin Pharmacol, 2009, 65(11): 1097-1103.
9. 郭伟, 王增智, 陈勇. VKORC1-1639G>A、CYP2C9*3基因多态性及年龄、体质量对汉族肺血栓栓塞症患者华法林稳定剂量的影响. 国际呼吸杂志, 2012, 32(21): 1621-1628.
10. Schalekamp T, Brassé BP, Roijers JF, et al. VKORC1 and CYP2C9 genotypes and phenprocoumon anticoagulation status: interaction between both genotypes affects dose requirement. Clin Pharmacol Ther, 2007, 81(2): 185-193.
11. Miyagata Y, Nakai K, Sugiyama Y. Clinical significance of combined CYP2C9 and VKORC1 genotypes in Japanese patients requiring warfarin. Int Heart J, 2011, 52(1): 44-49.
12. Limdi NA, Wadelius M, Cavallari L, et al. Warfarin pharmacogenetics: a single VKORC1 polymorphism is predictive of dose across 3 racial groups. Blood, 2010, 115(18): 3827-3834.
13. Geisen C, Watzka M, Sittinger K, et al. VKORC1 haplotypes and their impact on the inter-individual and inter-ethnical variability of oral anticoagulation. Thromb Haemost, 2005, 94(4): 773-779.
14. Kosaki K, Yamaghishi C, Sato R, et al. 1173C>T polymorphism in VKORC1 modulates the required warfarin dose. Pediatr Cardiol, 2006, 27(6): 685-688.
15. Yang J, Huang C, Shen Z, et al. Contribution of 1173C > T polymorphism in the VKORC1 gene to warfarin dose requirements in Han Chinese patients receiving anticoagulation. Int J Clin Pharmacol Ther, 2011, 49(1): 23-29.
16. Patillon B, Luisi P, Blanché H, et al. Positive selection in the chromosome 16 VKORC1 genomic region has contributed to the variability of anticoagulant response in humans. PLoS One, 2012, 7(12): 53049.
17. Limdi NA, Wadelius M, Cavallari L, et al. Warfarin pharmacogenetics: a single VKORC1 polymorphism is predictive of dose across 3 racial groups. Thromb Haemost, 2010, 115(18): 3827-3834.
18. Daneshjou R, Tatonetti NP, Karczewski KJ, et al. Pathway analysis of genome-wide data improves warfarin dose prediction. BMC Genomics, 2013, 14(Suppl 3): S11.
19. Huang SW, Chen HS, Wang XQ, et al. Validation of VKORC1 and CYP2C9 genotypes on interindividual warfarin maintenance dose: a prospective study in Chinese patients. Pharmacogenet Genomics, 2009, 19(3): 226-234.
20. Zhong SL, Yu XY, Liu Y, et al. Integrating interacting drugs and genetic variations to improve the predictability of warfarin maintenance dose in Chinese patients. Pharmacogenet Genomics, 2012, 22(3): 176-282.
21. 杨晶晶, 于锋, 葛卫红, 等. 华法林个体化剂量调整模型的建立和应用. 药学与临床研究, 2010, 18(3): 269-273.
22. Mushiroda T, Ohnishi Y, Saito S, et al. Association of VKORC1 and CYP2C9 polymorphisms with warfarin dose requirements in Japanese patients. Hum Genet, 2006, 51(3): 249-253.
23. Gan GG, Phipps ME, Lee MM, et al. Contribution of VKORC1 and CYP2C9 polymorphisms in the interethnic variability of warfarin dose in Malaysian populations. Ann Hematol, 2011, 90(6): 635-641.
24. Sangviroon A, Panomvana D, Tassaneeyakul W, et al. Pharmacokinetic and pharmacodynamic variation associated with VKORC1 and CYP2C9 polymorphisms in Thai patients taking warfarin. Drug Metab Pharmacokinet, 2010, 25(6): 531-538.
25. Gaikwad T, Ghosh K, Shetty S. VKORC1 and CYP2C9 genotype distribution in Asian countries. Thromb Res, 2014, 134(3): 1-8.

Chinese Journal of Evidence-Based Medicine

Study based on genotype and real warfarin dosage: suitable warfarin formula for Chinese population

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