Prevent warfarin "oversteer" with
DNA testing

Web Seminar: Pharmacogenetics in the Practice of Medicine

Order Pharmacogenetic Testing

Predict the maintenance dose of warfarin to within 1.5 mg per day, or less, by ordering a set of two DNA tests and using simple algorithms that take also take into account clinical and demographic factors.

Genetic variants detected by the tests are found in approximately half of patients and are the major contributor to variation in warfarin dose requirement.

The two genes CYP2C9 and VKORC1 are a model for the application of pharmacogenetic data because one controls the metabolism of the drug and the other controls the effective concentration requirement at the site of action.

• Cytochrome P450 2C9 is the most important enzyme in the metabolism of warfarin and greatly affects the half life and time to a stable dose. Without genetic testing it is not known if INR test results represent a steady state or one that is climbing.

  CYP2C9 genotype	Time to stable dose
  *1/*1 extensive(normal) metabolizer	4 - 5 days
  *1/*2 intermediate metabolizer	8 -10 days
  *1/*3, *2/*2, *3/*3 intermediate or poor metabolizer	12-15 days

  
  
• Vitamin K receptor, VKORC1, is the site of action of warfarin. The level of the enzyme is under genetic control according to the DNA sequence present in the control region of the gene. The more receptor present the more warfarin required.
  
  
• This graph illustrates the genotype based maintenance dose for a 160 cm tall, 66 year old female without significant drug interactions or other impairments. GG, GA and AA are the VKORC1 genotypes *1/*1 etc. are the CYP2C9 genotypes.

Here's what a blue ribbon FDA advisory panel has to say about the genetics of warfarin (Click here to view the meeting notes):

• Use lower doses of warfarin for patients with genetic variations in CYP2C9 and or VKORC1 that lead to reduced activities.
  
  
• Genotyping patients in the induction phase of warfarin therapy would reduce adverse events and improve achievement of stable INR.
  
  
• Existing evidence of the influence of CYP2C9 and VKORC1 genotypes warrants re-labeling of warfarin to include genetic test information.

 

The FDA and others are sponsoring clinical trials to prove the extent to which using DNA testing will reduce the morbidity and mortality associated with warfarin induced adverse bleeding events. Many scientists believe that the use of this testing will dramatically improve warfarin efficacy and safety. In fact, the FDA just updated the label to include genetic testing information. (Click here to view the release.) In the meantime you can order these tests now, and let your patients know that you're taking advantage of the most recent scientific discoveries.

Ordering Tests

Now you can add another dimension to providing safer and more efficacious care to your patients by ordering DNA Drug Sensitivity Testing™ for them. Call (800) 523-3080 for more information or to obtain collection kits, or visit how to order for test requisition forms and sample requirements.

Would you like an information package? Simply complete the request form.

References

Food and Drug Administration. New labeling information for Coumadin. Approved 1/22/2010.

Anderson JL, Horne BD, Stevens SM et al. Randomized trial of genotype-guided versus standard warfarin dosing in patients initiating oral anticoagulation. Circulation 2007;116:2563-70.

The International Warfarin Pharmacogenetics Consortium. Estimation of the warfarin dose with clinical and pharmacogenetic data.
N Engl J Med 2009;360:753-64.

Gage B, Eby C, Johnson J, Deych E et al. Use of Pharmacogenetic and Clinical Factors to Predict the Therapeutic Dose of Warfarin.  Clinical Pharmacology & Therapeutics 2008: 84, 326–331

Sconce EA et al.  The impact of CYP2C9 and VKORC1 genetic polymorphism and patients characteristics upon warfarin dose requirements: proposal for a new dosing regimen.  Blood 2005;106(7):2329-33.

Human Cytochrome P450 (CYP) Allele Nomenclature Committee; CYP2C9 allele nomenclature database at http://www.cypalleles.ki.se/cyp2c9.htm

Warfarin Genotyping Reduces Hospitalization Rates, Including Those Due to Bleeding or Thomboembolism Based on a study by the Medco Research Institute™ and Mayo Clinic, presented at the 2010 Annual Scientific Session of the American College of Cardiology; https://www.medcoresearch.com/community/pharmacogenomics/warfarin

Thomas P. Moyer et al.Warfarin Sensitivity Genotyping: A Review of the Literature and Summary of Patient Experience Mayo Clin Proc. • December 2009;84(12):1079-1094

Lee CR, Goldstein JA, Pieper JA. Cytochrome P450 2C9 polymorphisms: a comprehensive review of the in-vitro and human data. Pharmacogenetics 2002; 12:251-263

Cozza KL, Armstrong SC, Oesterheld JR (2003) Drug Interaction principles for Medical Practice. American Psychiatric Publishing Inc

Peyvandi F, Spreafico M, Siboni SM, Moia M and Mannucci PM.  Cyp2C9 genotypes and dose requirements during the induction phase of oral anticoagulation therapy. Clinical Pharmacology and Therapeutics 2004; 75(3):198-203

Joffe HV, Johnson XR, Longtine J, Kucher N and Goldhaber SZ. Warfarin dosing and Cytochrome P450 2C9 polymorphisms, Thromb Haemost; 2004 Jun;91(6):1123-8

Brockmoller J et.al. Pharmacogenetic diagnosis of cytochrome P450 polymorphisms in clinical drug development and in drug treatment. Pharmacogenetics. 2000:1:125-51.

Aynacioglu AS, et al. Frequency of cytochrome P450 CYP2C9 variants in a Turkish population and functional relevance for phenytoin. Br J Clin Pharmacol 1999; 48(3):409-415

Chang TK, et al. Enhanced cyclophosphamide and ifosfamide activation in primary human hepatocyte cultures: response to cytochrome P-450 inducers and autoinduction by oxazaphosphorines. Cancer Res 1997; 57(10):1946-54.

Hamman MA, Thompson GA, Hall SD. Regioselective and stereoselective metabolism of ibuprofen by human cytochrome P450 2C. Biochem Pharmacol 1997; 54(1):33-41.

Ho PC, et al. Influence of CYP2C9 genotypes on the formation of a hepatotoxic metabolite of valproic acid in human liver microsomes. Pharmacogenomics J 2003; 3(6):335-42.

Scordo MG, et al. Genetic polymorphism of cytochrome P450 2C9 in a Caucasian and a black African population. Br J Clin Pharmacol 2001; 52(4):447-450.

Miners J. CYP2C9 polymorphism: impact on tolbutamide pharmacokinetics and response. Pharmacogenetics 2002; 12(2):91-2.

Disclaimer: Do not alter the dosage amount or schedule of any drug you are taking without first consulting a qualified healthcare professional.
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Unless provided information expressly states that is was created by an MD or PharmD or cites another specific source, it was authored by Genelex employees that are not healthcare providers.