Andrew Guvetis Pharm.D. Candidate Nova Southeastern University 2012

Review Background

Review Pharmacogenetics of Warfarin

Discuss Current Data

Draw Conclusions

Initially introduced as a

rat pesticide in 1948

Approved for use in

humans in 1954

WARNING: BLEEDING RISK

JAMA. 2006;296(15):1858-1866.

Variable Response

Age

Weight Vitamin K Intake

Concurrent

Medications

S-Warfarin (more potent)

R-Warfarin

CYP2C9

CYP2C19

CYP3A4

CYP1A2

7-hydroxy-S-Warfarin

Hydroxylated R-Warfarin derivatives

Elimination CYP2C9*1 (wild-type)

CYP2C9*2

CYP2C9*3

Br J Clin Pharmacol. 1998;45:525-538.

Vitamin K (epoxidized)

Vitamin K (reduced)

Inactivated Proteins Factors II, VII, IX, and X

Proteins C, S, and Z

Activated Clotting Factors

WARFARIN

VKORC1 GG

VKORC1 AG (wild-type)

VKORC1 AA

Blood. 2005;105:645-649.

Patients possessing variant genotypes:

• achieve stable anticoagulation on lower warfarin doses4 • are at significantly increased risk of a serious or life-threatening bleeding event5

Lancet. 1999;353(9154):717-719. JAMA. 2002;287(13):1690-1698.

• A single VKORC1 variant allele explains 30% of variation in dose.

• CYP2C9 variants *2 and *3 explain approx. 12% of the variation.

Blood. 2008;113:784-792.

•Derivation Cohort (n=4043) •Validation Cohort (n=1009)

•Algorithm more accurately identified pts requiring: ≤21 mg/week (49.4% v. 33.3%; P<0.001) ≥49 mg/week (24.8% v. 7.2%; P<0.001)

N Engl J Med. 2009;360:753-764.

Algorithm is available for download at: www.pharmgkb.org

Quality data is lacking.

2011 Study: Pharmacogenetic model accurately identified therapeutic dose more often than clinical algorithms.

65.3% v. 34.7%; P<0.001 Genet Med. 2011;13(6):509-518.

1. Budnitz DS, Pollock DA, Weidenbach KN, Mendelsohn AB, Schroeder TJ, Annest JL. National surveillance of emergency department visits for outpatient adverse drug events. JAMA. 2006;296(15):1858-1866.

2. Miners JO, Birkett DJ. Cytochrome P4502C9: an enzyme of major importance in human drug metabolism. Br J Clin Pharmacol. 1998;45:525-538.

3. D’Andrea G, D’Ambrosio RL, Di Perna P, Chetta M, Santacroce R, Brancaccio V et al. A polymorphism in the VKORC1 gene is associated with an interindividual variability in the dose-anticoagulant effect of warfarin. Blood. 2005;105:645-649.

4. Aithal GP, Day CP, Kesteven PJL, Daly AK. Association of polymorphisms in the cytochrome P450 CYP2C9 with warfarin dose requirement and risk of bleeding complications. Lancet. 1999;353(9154):717-719.

5. Higashi MK, Veenstra DL, Kondo LM, Wittkowsky AK, Srinouanprachanh, Farin FM et al. Association between CYP2C9 genetic variants and anticoagulation-related outcomes during warfarin therapy. JAMA. 2002;287(13):1690-1698.

6. Wadelius M, Chen LY, Lindh JD, Eriksson N, Ghori MJR, Bumpstead S. The largest prospective warfarin-treated cohort supports genetic forecasting. Blood. 2008;113:784-792.

7. International Warfarin Pharmacogenetics Consortium. Estimation of the warfarin dose with clinical and pharmacogenetic data. N Engl J Med. 2009;360:753-764.

8. Burmester JK, Berg RL, Yale SH, Rottscheit CM, Glurich IE, Schmelzer JR et al. A randomized controlled trial of genotype-based Coumadin initiation. Genet Med. 2011;13(6):509-518.

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Thank you for your attention!