Health Care Professional Benefits
Clinical importance of pharmacogenetics.
Pharmacogenetics links physiological variations in drug metabolism and response to genetic variations in the genes which encode drug metabolizing enzymes and receptor proteins. Such genetic differences can profoundly alter the relationship between drug-dosage, plasma concentrations, and drug response in individual patients, creating confusing clinical scenarios and producing severe side effects. The relationship between many genetic variations and their influence on drug response have now been identified and can be applied to improved patient care.
How can I incorporate Pharmacogenetics information into my practice?
Pharmacogenetic testing is currently being applied in two ways, as a diagnostic tool and as a predictive or screening tool.
Diagnostic Pharmacogenetics Testing
Pharmacogenetics are applied as a diagnostic tool to help explain certain medical conditions, such as an adverse drug reaction (ADR). When ordering pharmacogenetic testing on these patients you accomplish three things:
1. You learn the physiological reason for your patient's condition and have solid evidentiary support for your clinical decisions.
2. You can provide justification to third party payors for prescribing higher medication doses or changing drug choices to more expensive or non-standard options.
3. You can provide an explanation to the patient for the trouble they've been having and alleviate their fears that somehow they are doing something wrong.
For example, consider atomoxetine (Strattera). Atomoxetine is metabolized by the enzyme cytochrome P4502D6 (CYP2D6). Approximately 40% of the population are carriers of a CYP2D6 allele that either dramatically reduces or increases plasma clearance. Diagnostic testing is available to determine whether or not your patient is a reduced or poor metabolizer, or if they metabolize Atomoxetine at a greater than average rate.
Several Atomoxetine side effects are more common among children with limited CYP2D6 activity. These same side effects are also evident when the plasma concentrations of Atomoxetine are consistently higher than that associated with a favorable clinical response. These side effects include decreased appetite, sedation and depression, and are listed in the Atomoxetine product label.
Individuals with decreased CYP2D6 activity can be identified through DNA analysis. For these patients, steady-state, which is the consistent relationship between dosage and resulting plasma concentration, is delayed by as much as 4 days and their plasma concentrations are on average four to five-fold higher than in patients with normal SYP2D6 activity. Upon discontinuation of therapy, these patients experience delayed clearance while plasma concentrations of Atomoxetine persist at a level above that required for desired therapeutic effects.
You can minimize the risk of these side-effects by testing your patients to determine whether or not they have a CYP2D6 enzyme deficiency. This information allows you to anticipate that lower dosages will be required to achieve the same plasma concentrations as a patient with no enzyme deficiency at the standard dose.
An alternate scenario arises in those individuals who have a CYP2D6 duplication (3 or more copies of the active gene). These patients rapidly eliminate Atomoxetine and may require higher dosages to achieve similar drug exposure as those patients with average metabolic activity at standard doses.
Please visit the FDA web site for further discussion of genomics and personalized medicine and a list of other medications and their associated genomic biomarkers.
Screening Pharmacogenetics Testing
As a screening tool pharmacogenetic testing is carried out in the absence of a pre-existing medical condition. In these cases, pharmacogenetic testing is used to identify the risk of future problems in the hopes of preventing them. This approach may be indicated in several scenarios:
Screening the family members of patients who are known to have had an ADR.
Testing patients with a history of therapeutic failure, but who need to receive the problem drug again.
It may be used in a manner similar to blood typing. The time when the results will be needed can not always be predicted, but having the information in an emergent situation has an enormous potential benefit.
For example, consider the anticoagulant warfarin (Coumadin). Warfarin is a racemic mixture of R- and S- warfarin. The S-warfarin enantiomer is considered to be the primary active moiety. S-warfarin is metabolised via the cytochrome P4502C9 enzyme (CYP2C9). Approximately 30 to 40% of individuals inherit one or more alleles that lead to decreased CYP2C9 activity. Decreased CYP2C9 is unequivocally associated with increased risk of severe bleeding and increased time to stable therapy. The anticoagulation effects of S-warfarin result from inhibition of the vitamin K epoxide reductase. Recently, inherited genetic variation in the expression of Vitamin K Epoxide Reductase Component Protein 1 (VKORC1) has been clearly associated with decreased maintenance dose requirement and an increased risk of bleeding when standard dosages are administered.
Our laboratory is equipped to apply a mathematical model similar to ones in the published literature, which makes our lab capable of estimating the most appropriate maintenance dose for your patients based in part on diagnostic testing of CYP2C9 and the VKORC1 genetic variants. This knowledge limits the potential for unintentional overdose.
The feasibility of this approach in limiting the risk of above-range INRs and bleeding events and in decreasing the time required to titrate patients to stable therapy has been acknowledged by the Clinical Pharmacology Advisory Committee reporting to the FDA. The manufacturer of Coumadin has now includes this information in the Coumadin product label.
Although at this time the results of prospective studies are not available to systematically document improved patient care resulting from application of these technologies, there are a few generally recognized and fundamental concepts that can be immediately applied to this problem.
The first consideration is that studies have demonstrated that INRs within the therapeutic range occur on average after four days of continuous therapy. Likewise, differences in dose requirement due to decreased CYP2C9 activity are not apparent until the fourth day of therapy. It is likely, therefore, that the knowledge gained by diagnostic testing will be of most value within this time frame and that standard approaches to the initation of anticoagulation therapy are still appropriate.
Secondly, it is a fundamental concept in pharmacology that a patient's response to a specific dosage is most reliably assessed once that dosage has been administered for a sufficient period of time for there to be a consistent relationship between the dosage administered and the resulting plasma drug concentrations. This is the situation referred to as "steady state". The time required to reach steady state is fundamentally linked to the plasma half-life of the medication. The average half-life of S-warfarin ranges from 3 days for individuals with full CYP2C9 activity to 12 days or longer for patients with decreased CYP2C9 activity. In practice, this means that the most reliable measurements of the INR will be those obtained once steady state is achieved after any change in dosage.
You may have noticed in your practice that a patient may undergo consistent dosing for several days and the INR is repeatedly within the target range, but when the patient returns in a week or two, the INR is inexplicably beyond the upper limit of the target range. In response, you may have decided to decrease the dosage and measure the INR again one, two or three days later. At this time, the INR may still be elevated and you may feel the need to further reduce the dosage. When your patient returns for monitoring you may find their INR is now below the target range... the tedious titration process continues.
This "over-steer" in dosage titration can be attributed to the fact that for this individual, there is a delay in reaching the steady-state situation beyond what your experience is with the majority of patients. The knowledge that your patient has a deficiency in the metabolism of this medication can help you interpret the meaning of INR measurements and allow you to develop a monitoring strategy that takes this delay into account. This process can facilitate more consistent care for your patient.
Therefore, screening your patients gives you insight into their metabolic capacity during the early phase of therapy, and provides you with fundamental information supported by the classical principles of pharmacology. This can improve both the lives of your patients, and the effectiveness of your practice.
Please visit the FDA web site for further discussion of genomics and personalized medicine and a list of other medications and their associated genomic biomarkers.
The ultimate goal of pharmacogenetics is to provide completely individualized therapeutics. The field is not completely mature in that respect; however, for a limited number of therapeutic compounds there exists a good dose-adjustment guideline. We have included them on this website. The list is ever-expanding although at this time there is a lack of published prospective studies to determine the clinical effects of pharmacogenetically guided dosing. This deficiency has been identified, and we hope the results from large, multi-center trials will soon be available. We will be sure to make these studies available to you here.