Integration of Genetic, Clinical, and INR Data to Refine Warfarin Dosing

被引：172

作者：

Lenzini, P. ^{[1
]}

Wadelius, M. ^{[2
]}

Kimmel, S. ^{[3
,4
]}

Anderson, J. L. ^{[5
]}

Jorgensen, A. L. ^{[6
]}

Pirmohamed, M. ^{[7
]}

Caldwell, M. D. ^{[8
]}

Limdi, N. ^{[9
,10
]}

Burmester, J. K. ^{[11
]}

Dowd, M. B. ^{[12
]}

Angchaisuksiri, P. ^{[13
]}

Bass, A. R. ^{[14
]}

Chen, J. ^{[3
,4
]}

Eriksson, N. ^{[2
,15
]}

Rane, A. ^{[16
]}

Lindh, J. D. ^{[16
]}

Carlquist, J. F. ^{[5
]}

Horne, B. D. ^{[5
]}

Grice, G. ^{[17
]}

Milligan, P. E. ^{[1
]}

Eby, C. ^{[1
,18
]}

Shin, J. ^{[19
,20
]}

Kim, H. ^{[19
,20
]}

Kurnik, D. ^{[21
]}

Stein, C. M. ^{[21
]}

McMillin, G. ^{[22
]}

Pendleton, R. C. ^{[22
]}

Berg, R. L. ^{[23
]}

Deloukas, P. ^{[24
]}

Gage, B. F. ^{[1
]}

机构：

[1] Washington Univ, Dept Internal Med, St Louis, MO 63130 USA

[2] Uppsala Univ, Dept Med Sci, Uppsala, Sweden

[3] Univ Penn, Dept Med, Philadelphia, PA 19104 USA

[4] Univ Penn, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA

[5] Intermt Med Ctr, Cardiovasc Dept, Salt Lake City, UT USA

[6] Univ Liverpool, Ctr Med Stat & Hlth Evaluat, Liverpool L69 3BX, Merseyside, England

[7] Univ Liverpool, Dept Pharmacol & Therapeut, Liverpool L69 3BX, Merseyside, England

[8] Marshfield Clin Fdn Med Res & Educ, Dept Surg, Marshfield, WI USA

[9] Univ Alabama, Dept Neurol, Birmingham, AL 35294 USA

[10] Univ Alabama, Dept Epidemiol, Birmingham, AL USA

[11] Marshfield Clin Res Fdn, Ctr Human Genet, Marshfield, WI USA

[12] Kaiser Permanente, Clin Pharm Cardiac Risk Serv, Denver, CO USA

[13] Mahidol Univ, Ramathibodi Hosp, Dept Med, Bangkok 10700, Thailand

[14] Hosp Special Surg, Dept Med, New York, NY 10021 USA

[15] Univ Uppsala Hosp, Uppsala Clin Res Ctr UCR, Uppsala, Sweden

[16] Karolinska Inst, Div Clin Pharmacol, Stockholm, Sweden

[17] St Louis Coll Pharm, Dept Pharm Practice, St Louis, MO USA

[18] Washington Univ, Dept Pathol, St Louis, MO 63130 USA

[19] Inje Univ, Coll Med, Pharmacogenet Res Ctr, Pusan, South Korea

[20] Inje Univ, Coll Med, Dept Pharmacol, Pusan, South Korea

[21] Vanderbilt Univ, Dept Med, Nashville, TN USA

[22] Univ Utah, Dept Internal Med, Salt Lake City, UT 84112 USA

[23] Marshfield Clin Fdn Med Res & Educ, Biomed Informat Res Ctr, Marshfield, WI USA

[24] Wellcome Trust Sanger Inst, Dept Human Genet, Hinxton, England

来源：

CLINICAL PHARMACOLOGY & THERAPEUTICS | 2010年 / 87卷 / 05期

基金：

美国国家卫生研究院; 英国惠康基金;

关键词：

REDUCTASE COMPLEX SUBUNIT-1; HEART-VALVE REPLACEMENT; ORAL ANTICOAGULATION; ORTHOPEDIC PATIENTS; AFRICAN-AMERICANS; DOSE REQUIREMENTS; VKORC1; GENOTYPES; RANDOMIZED-TRIAL; CYP2C9; THERAPY;

D O I：

10.1038/clpt.2010.13

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

Well-characterized genes that affect warfarin metabolism (cytochrome P450 (CYP) 2C9) and sensitivity (vitamin K epoxide reductase complex 1 (VKORC1)) explain one-third of the variability in therapeutic dose before the international normalized ratio (INR) is measured. To determine genotypic relevance after INR becomes available, we derived clinical and pharmacogenetic refinement algorithms on the basis of INR values (on day 4 or 5 of therapy), clinical factors, and genotype. After adjusting for INR, CYP2C9 and VKORC1 genotypes remained significant predictors (P < 0.001) of warfarin dose. The clinical algorithm had an R-2 of 48% (median absolute error (MAE): 7.0 mg/week) and the pharmacogenetic algorithm had an R-2 of 63% (MAE: 5.5 mg/week) in the derivation set (N = 969). In independent validation sets, the R2 was 26-43% with the clinical algorithm and 42-58% when genotype was added (P = 0.002). After several days of therapy, a pharmacogenetic algorithm estimates the therapeutic warfarin dose more accurately than one using clinical factors and INR response alone.

引用

页码：572 / 578

页数：7

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