Dose adjustment Chart

Best described PG cases

Interpretive Comments

WE EXPECT OUR CLIENTS TO SEEK PROFESSIONAL ADVICE CONCERNING ANY MEDICAL OR LEGAL ACTIONS THAT MIGHT BE SUGGESTED BY THE INFORMATION WE OFFER.

The information below can help you understand and apply the results of the DNA Prescription Drug Reaction Test currenty offered by PGXL Laboratories. Our tests spot individual genetic variants in the two most important drug metabolizing enzymes: Cytochrome P-450's CYP2D6 and CYP2C9.

More than half of the population has one or more serious defects in the genes coding for these enzymes. Recent research shows that genetic variation in the drug metabolizing system is the singlemost important factor affecting a patient's response to drugs. The information PGXL Laboratories provides can help you determine the appropriateness and dosage of roughly a third of the most commonly prescribed drugs. To determine if medications are metabolized through these pathways, utilize the following database: Gentest's Human P450 Metabolism Database.

Testing places individuals in one of four categories:

• 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.
• Intermediate metabolizers (IM) may require lower than average drug dosages for optimal therapeutic response. In addition, multiple drug therapy should be monitored closely.
• 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.
• 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.

Cytochrome P-450 2D6

Phenotype prevalence is 10 % PM, 7% UM, and 35% IM.

Therapy Modification

PM

Cytochrome P-450 2C9

Phenotype prevalence is 3.7% PM, 38% IM.

Therapy Modification

PM

Reduce dosage 3-5 fold.

IM

Start IM's at lowest efficacious dose, avoid multiple drug therapy that inhibits or activates through the same pathway.

Therapeutic drug monitoring in PM and IM subjects is highly recommended. Again standard measures of efficacy (INR for Warfarin or therapeutic target interval for Phenytoin, for example) can be applied to ensure optimal therapy.

References

http://gentest.com/human_p450_database/

Linder MW, Valdes R Jr. Pharmacogenetics in the practice of laboratory medicine. Mol Diagn. 1999 Dec;4(4):365-79. Review. PMID: 10671647 [PubMed - indexed for MEDLINE]

New Pharmacogenetic Test Simplifies Coumadin (warfarin) Management

How are patients currently managed on warfarin therapy?

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.

How does an individual’s genetic make-up effect how much warfarin should be administered?

In addition to the physical characteristics mentioned above, functional characteristics also influence the most appropriate dose of warfarin. 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 cytochrome P450 2C9 (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.

How can this information be applied?

The difference in warfarin dose that is affected by the patient’s metabolism or the amount of drug needed for effect do not become apparent until the four to fifth day of therapy (Peyvandi F et al. Clin Pharm Ther 2004;75:198-203). Therefore, standard approaches to initiating treatment do not need to be postponed. A sample of blood can be collected for determination of CYP2C9 and VKORC1 status on the first day of therapy. Preferably the results of testing should be applied to dose selection on or shortly after the fifth day of therapy.

What services are offered by PGXL?

PGXL is owned and operated by internationally recognized experts in the field of clinical pharmacogenetics. PGXL is a private entity derived from the University of Louisville Pharmacogenetics Diagnostics Laboratory which was the first CLIA approved laboratory to exclusively offer pharmacogenetic diagnostic services.

PGXL can perform the diagnostic testing necessary for estimating individual maintenance dosages and can provide this service to most clients with a three day turnaround time once the specimen is received in our laboratory.

PGXL can apply a dose prediction algorithm developed by affiliated scientists at the University of Louisville and estimate the maintenance dose for most individuals. This information can then be applied by the healthcare provider within the current standard of therapy clinical context.

What is the scientific community saying about these services?

In November of 2005, the clinical pharmacology advisory committee reporting to the FDA reviewed the current literature surrounding the application of CYP2C9 and VKORC1 testing to treatment of patients with warfarin. At that meeting, the committee unanimously agreed that “…sufficient mechanistic and clinical evidence exists to support the recommendation: to use lower doses of warfarin for patients with genetic variations in CYP2C9 and or VKORC1 that lead to reduced activities”. And genotyping patients in the induction phase of warfarin therapy would reduce adverse events and improve achievement of stable INR? Eight out of ten committee members agreed “…that existing evidence of the influence of CYP2C9 and VKORC1 genotypes warrants re-labeling of warfarin to include genomic and test information.

Based on official meeting transcripts which can be found at: http://www.fda.gov/ohrms/dockets/ac/cder05.html#PharmScience

Is this testing likely to be cost effective?

There is a high likelihood that this testing will improve patient safety while providing significant savings to the healthcare system. Recent reports indicate that 70 to 100 severe bleeding events occur each year for every 1000 patients treated with warfarin (Higashi et al. JAMA 2002;287:1690-98; Margaglione M et al. Thromb Haemost 2000;84:775-8). Each of these events can result in an average hospital stay of 6 days and average healthcare costs of $16,000.00 for each event (Fanikos J et al Am J Cardiology 2005;96:595-8). PGXL charges $35.00 to process the sample, $ 266.00 for each CYP2C9 and VKORC1 test thus the total cost of testing is $ 567.00. If we apply this to a patient population of 1000 patients treated for a year, cost effectiveness will be achieved if 33 to 47% of the anticipated number of bleeding events are avoided. Any events avoided beyond this will have obvious positive benefits for the patient and directly reduce the financial burden on the healthcare system.

Are these laboratory services covered by health insurance?

This year, the American Medical Association (AMA) recommended to the Centers for Medicare & Medicaid Services (CMS) to establish CPT codes and reimbursement schedules which can be applied to pharmacogenetic diagnostics. The appropriate coding is dependent upon the technology used by the laboratory. The anticipated reimbursement based on the 2006 Kentucky Medicare and Medicaid fee schedule for CYP2C9 and VKORC1 as performed by PGXL is 70% of the total charge. Private insurance companies such as Anthem, Humana and others (By Lisa Barrett Mann, Special to The Washington Post, Tuesday, April 18, 2006; Page HE01) have covered costs for testing for the majority of our clients who submitted for coverage.

Disclaimer

The content of this web site is for public use, free of charge, and for information only. It is not intended to be used in any other way. The authors disclaim any liability, loss, injury, or damage incurred as a consequence, directly or indirectly, of the use and application of any of the content of this web site.

The information presented on this site is intended as general health information and as an educational tool. It is not intended as medical advice. Only a physician, pharmacist, or other healthcare professional should advise a patient on medical issues and should do so using a medical history and other factors identified and documented as part of the health professional/patient relationship.