Pharmacogenetics and Warfarin

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Pharmacogenetics and Warfarin

  1. 1. Andrew GuvetisPharm.D. CandidateNova Southeastern University 2012
  2. 2. Review BackgroundReview Pharmacogenetics of WarfarinDiscuss Current DataDraw Conclusions
  3. 3. Initially introduced as arat pesticide in 1948 Approved for use in humans in 1954 WARNING: BLEEDING RISK
  4. 4. JAMA. 2006;296(15):1858-186
  5. 5. Weight Vitamin K Intake Variable ResponseAge Concurrent Medications
  6. 6. CYP2C9 7-hydroxy-S-S-Warfarin(more potent) Warfarin CYP2C9*1 (wild-type) CYP2C9*2 Elimination CYP2C9*3 CYP2C19 CYP3A4 HydroxylatedR-Warfarin R-Warfarin CYP1A2 derivatives Br J Clin Pharmacol. 1998;45:525-538.
  7. 7. VKORC1 GG VKORC1 AG (wild-type)WARFARIN VKORC1 AA Vitamin K Vitamin K (epoxidized) (reduced) Inactivated Proteins Activated ClottingFactors II, VII, IX, and X Factors Proteins C, S, and Z Blood. 2005;105:645-649.
  8. 8. Patients possessing variant genotypes: • achieve stable anticoagulation on lower warfarin doses4 • are at significantly increased risk of a serious or life-threatening bleeding event5Lancet. 1999;353(9154):717-719. JAMA. 2002;287(13):1690-1698.
  9. 9. • A single VKORC1 variantallele explains 30% ofvariation in dose.• CYP2C9 variants *2 and *3explain approx. 12% of thevariation. Blood. 2008;113:784-792.
  10. 10. •Derivation Cohort (n=4043)•Validation Cohort (n=1009)•Algorithm more accurately identifiedpts 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.
  11. 11. Algorithm is available fordownload at:www.pharmgkb.org
  12. 12. Quality data is lacking.2011 Study:Pharmacogenetic model accuratelyidentified therapeutic dose moreoften than clinical algorithms.65.3% v. 34.7%; P<0.001 Genet Med. 2011;13(6):509-518.
  13. 13. 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.
  14. 14. http://www.immortalhumans.com/genes-%E2%80%93-is-it-the-key-to-longevity-%E2%80%93-a-rise-in-centenarians/http://christinevanbelle.blogspot.com/2011/01/i-wish-it-was-ghost.htmlhttp://www.fda.gov/Safety/Recalls/ucm253770.htm http://www.sxc.hu/photo/1334534
  15. 15. http://www.sxc.hu/photo/987819http://mysnoringsolutions.info/anti-snoring-pills/http://www.bigstockphoto.com/image-11684888/stock-photo-young-medical-doctor-thinking
  16. 16. Thank you foryour attention!

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