The field of pharmacogenomics seeks to define five primary outcomes:
- clinical response and differentiation;
- risk identification;
- dose selection guidance;
- susceptibility, resistance, and differential disease diagnosis; and
- polymorphic drug targets.
A pharmacogenomic test result, therefore, is much more informative than traditional therapeutic drug monitoring. A pharmacogenomic test result can inform physicians on the best therapeutic selection for an individual, including dose adjustment based upon a metabolic profile. Thus, the pharmacogenomic test has the potential to reduce adverse reactions or even death through accidental overdose. In many cases, the accidental overdose is the result of an individual’s genetically defined ability to metabolize particular compounds.
An excellent example of this is warfarin, which is used as an anticoagulant to protect against heart attack or stroke. Warfarin is taken by 42 million in the US each year, and dose adjustment is historically made by physicians using prothrombin (Rettie and Tai, 2006
; Gak and Halkin, 2008
; Babic et al., 2009
; Daly, 2009
; Tan et al., 2010
). The dose is adjusted up or down as dictated by weekly or monthly tests to maintain optimal blood levels, since a suboptimal dose will not prevent the formation of embolisms, while an overdose can cause excessive bleeding. Pharmacogenomic testing has shown that human response to warfarin is dictated by several single nuclear polymorphisms (SNPs) located in the CYP2C9 gene. These SNPs have been defined and clinically validated. Currently, manufacturers marketing the drug include genetic information in the product labeling.
In preliminary studies utilizing genomic DNA obtained from oral fluids with a combination of custom buffers and commercially available membranes, we were able to amplify regions of DNA involved in sensitivity to warafin. In a locked nucleic acid format, the CYP2C9*2 and CYP2C9*3 mutations were distinguished from control wild-type sequences (Organtini K, Gonzalez JM, and Niedbala RS, unpublished observations), thus demonstrating proof-of-concept.
If the goal is to expand the use of oral-based diagnostics, then pharmacogenomics is a natural area for expansion. Test collection with an oral sample is as easy and non-invasive as dreamed of decades ago by some investigators. The key difference is that pharmacogenomics is based upon the collection of cells from which DNA can then be extracted, amplified, and analyzed. The mouth routinely sheds cells, or they may be easily loosened and collected by gentle brushing. The stability of DNA during collection and storage is the first challenge. Some commercial kits have been introduced, but they are expensive and not user-friendly. It is anticipated that the commercial opportunity for the collection of DNA will drive innovation, and new collectors are already being developed and introduced.
The second component to facilitate the use of oral fluid pharmacogenomics is the development of standard procedures to isolate the DNA from the collector and to amplify relevant genes efficiently. Thus far, there is only limited information outlining thoroughly evaluated procedures. Finally, the outcomes from the testing must be shown to be equivalent to current practices. Since DNA can be obtained from any cell in the body, there is theoretically no difference between samples collected from blood and those collected from the mouth. Oral-based pharmacogenomic testing is a natural extension of existing techniques. Additionally, there is a great deal of support for pharmacogenomic testing among regulatory bodies in the US. The successful use of oral fluids in this arena would expand the market for testing to millions of new opportunities.
There are several key milestones that will improve the chance for oral testing to become a standard in this rapidly developing field:
- The literature shows that blood or oral fluids are viable for pharmacogenomics.
- Oral fluids collection and processing costs are competitive with those for blood.
- Oral fluids are included in pharmacogenomic regulations or guidance documents.
The last point above is perhaps the most important. Scientists are free to publish debate and define the parameters that will ensure quality scientific results. These results are vetted in the peer review process. However, the potential value of oral fluids included in guidance documents or regulations cannot be underestimated. Non-scientists will often look to such documents to avoid potential legal problems. Additionally, healthcare systems must also have a defined way to pay for the sampling and testing. Thus, successful use of oral testing for pharmacogenomics is technically feasible but still requires additional carefully controlled studies to create the body of evidence needed to obtain regulatory approval.