Coumadin (warfarin) is the most commonly prescribed anticoagulant for the treatment and prevention of thromboembolic events. The dose of warfarin required to maintain a safe degree of anticoagulation ranges from 2 mg/day or lower for some individuals to 10 mg per day or higher for others. Patients who are not taking the dose that is right for them are at an increased risk for severe toxicity or an inadequate response. Currently, clinicians anticipate maintenance dose requirements based on the patients physical characteristics such as age, gender and weight and monitor the therapeutic effects closely by measuring the INR. However these physical characteristics do not account for the major sources of variation in dose requirement. Therefore the clinician must adjust the warfarin dosage when the INR is not within the safe range for anticoagulation. This can be a lengthy trial and error process where the patient is at increased risk until the most appropriate dosage for that patient is determined.
The major functional characteristics which influence the warfarin dose are how rapidly the individual metabolizes warfarin and how much warfarin is required in the body to inhibit to formation of clotting factors. These characteristics can not be assessed without specific diagnostic testing.
The active component of warfarin is metabolized by CYP2C9. Up to 35% of the population inherits a form of the CYP2C9 gene which results in a CYP2C9 enzyme deficiency. A deficiency in CYP2C9 causes slow metabolism and higher than expected concentrations of the active drug to accumulate. This increased warfarin concentration in the body increases the risk of bleeding.
Warfarin inhibits the formation of active clotting factors by inhibition of vitamin K epoxide reductase complex subunit 1 (VKORC1). Inherited differences in VKORC1 increase or decrease the amount of warfarin needed to inhibit the formation of the clotting factors. When the amount of warfarin exceeds what is needed, the risk of bleeding is increased.
The FDA's Clinical Pharmacology Subcommittee of the Advisory Committee on Pharmaceutical Science voted in November 2005 in favor of changing Warfarin's label to reflect the fact that genetic information from two genes, CYP450 2C9 and VKORC1, could be useful in deciding a patient's individual dose.
"Does the committee believe that genotyping patients in the induction phase of warfarin therapy would reduce adverse events and improve achievement of stable INR?
a. in patients with genetic variations in CYP2C9
b. in patients with genetic variations in VKORC1
By consensus/unanimously without a vote, the subcommittee adopted the revised language of the introductory section of the question. The subcommittee deleted the words, “some or all” before the word “patients” and replaced the phrase, “”prior to beginning” with “in the induction phase”.
By consensus/unanimously without a vote, the subcommittee agreed with both subparts a. and b. to the question."
Source [fda.gov]
Our CYP2C9 & VKORC1 Molecular Assays are accredited assays (ISO17025 – Belac) that detect the different variant to determine the metabolism status.
List of variants analysed:
CYP2C9 |
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Variant |
Alleles |
Activity |
Wild type |
*1 |
Normal |
VKORC1 |
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Variant |
Alleles |
Activity |
Wild type |
|
Normal |
Metabolism status :
EM – IM – PM – UM |
CYP2C9 Prevalences in Caucasian |
Extensive metabolizers (EM) represent the norm for metabolic capacity. Genotypes consistent with the EM phenotype include two active forms of the gene producing the drug metabolizing enzyme and therefore posses the full complement of drug metabolizing capacity. Generally, extensive metabolizers can be administered drugs which are substrates of the enzyme following standard dosing practices. |
67% |
Intermediate metabolizers (IM) may require lower than average drug dosages for optimal therapeutic response. In addition, multiple drug therapy should be monitored closely. |
30% |
Poor metabolizers (PM) are at increased risk of drug-induced side effects due to diminished drug elimination or lack of therapeutic effect resulting from failure to generate the active form of the drug. Genotypes consistent with the PM phenotype are those with no active genes producing the drug metabolizing enzyme. These individuals have a deficiency in drug metabolism. |
3% |
Ultra-extensive metabolizers (UM) may require an increased dosage due to higher than normal rates of drug metabolism. Simultaneously treating with medication that inhibits metabolization has also proven effective. Genotypes consistent with UM phenotype include three or more active genes producing the drug metabolizing enzyme and therefore have increased metabolic capacity. |
0% |