Practical Applicability, How can I incorporate Pharmacogenetics information into my practice, should I?
Pharmacogenetic testing is currently being applied in 2 ways, as a diagnostic tool and as a predictive or screening tool.
Diagnostic Pharmacogenetics Testing
When applied as a diagnostic tool there is a medical condition such as an ADR for which pharmacogenetic information may provide an explanation. By ordering pharmacogenetic testing on these patients you accomplish three things.
- Find out a physiological reason and evidence to support your clinical decisions,
- Provide proof to third party payers for higher medication doses, or drug changes to potentially more expensive or non-standard options.
- Provide an explanation to the patient for the trouble they've been having, thereby allying fears that somehow they are doing something wrong.
Screening Pharmacogenetics Testing
As a screening tool pharmacogenetic testing is carried out in the absence of a pre-existing medical condition. Instead pharmacogenetic testing is used to identify potential future problems in the hopes of preventing them from occurring. Examples of when this approach may be indicated would include;
- Screening family members of patients known to have had an ADR.
- Testing patients who have a history of therapeutic failure, but need to receive the problem drug again.
- More generally used 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.
The ultimate goal of pharmacogenetics is completely individualized therapeutics. The field is not mature in that respect. For a limited number of therapeutic compounds there exists good dose adjustment guidelines. We have included them on this website (link to dose adjustments). That list is ever-expanding. It is true however that at this time there is a lack of published prospective studies to determine the clinical effects of pharmacogeneticly guided dosing. This deficiency has been identified, and hopefully the results from large, multi-centered trials will soon be available. At that time, we will make them available here.
Pharmacogenetics vs Pharmacogenomics, what's the difference?
Pharmacogenetics and Pharmacogenomics are often used interchangeably. However there is a conceptual difference between the terms. Pharmacogenetics is the study of interindividual variations in DNA sequence related to drug response. Pharmacogenomics is the study of the variability in expression of individual genes relevant to disease susceptibility as well as drug response at a cellular, tissue, individual or population level. The second term is broadly applicable to drug design, discovery and clinical development. The practical difference for clinicians is patient genetic testing falls under pharmacogenetics.
Clinical importance of pharmacogenetics.
- Genetic variation resulting in loss or increase of enzyme activity can have profound effects on the relationship between drug-dosage and observed plasma concentrations.
- The concentration of a drug in plasma at steady state is equal to the dose divided by the clearance (Cp=dose/cl).
- If PK genetic variation results in clearance rate to be reduced by ½, to maintain the same concentration in plasma, the dose must be halved.
- In cases of pain management therapy proper dosing is critical because failure could result in the breakthrough of pain much sooner than the next dose of analgesic is due. Such dramatic pharmacokinetic differences may result in severe toxicity or therapeutic failure if they are not known prior to therapy initiation.
Other important web links
- National Institute of General Medical Sciences pharmacogenetics page (at the NIH)
- Studies indication dosing adjustments based on Pharmacogenetics variation
- Exhibit developed for the Tech Museum of Innovation by EPIC: Electronic Publishing Instructional Curriculum at the University of California, Santa Cruz
- Genetic Science Learning Center at the Eccles Institute of Human Genetics, University of Utah
Genotype vs. Phenotype
- A person requiring therapeutic compounds is not a discreet set of genotypes to be tested, rather is the sum of all variation in his/her genome as well as the effect of other environmental factors. (Link to the "Human Genome Project")
- The observed phenotype is the result of liver and/or kidney function, age, female gender together with the genotype and any genetic variation. Therefore a complete history and physical, including concomitant medications is essential. (The Merck manual of Geriatrics)
- The ultimate goal for pharmacogenetic information to be practically applied is a holistic approach to totally individualized selection of therapeutic agents, rather than one-size-fits all approach. (Center for Drug Evaluation and Research at the USFDA)