Vol. 22 • Issue 6 • Page 16
Toxicology
The increased use of genetic testing and whole genome sequencing in recent years has given rise to a new trend in healthcare – personalized medicine. By determining on a genetic level what disorders patients may be susceptible to and which medications will draw the best response, doctors can prescribe treatment with greater confidence in its efficacy, avoiding adverse effects, improving outcomes, and possibly bringing down overall healthcare utilization. This holds value especially for the world of pain management, where many drugs have addictive qualities and the therapeutic window may be narrow, meaning a higher risk for adverse outcomes.
Pharmacogenetic testing allows clinicians to search for genetic ðvariations in the enzymes that control drug activation and metabolism, and therefore predict what a patient’s unique response to that drug might be.
“The goal of pharmacogenetic testing is to identify or predict responses, matching patients to the proper medication as a means of delivering personalized therapy,” said Angela Huskey, Pain Educator of the Year and associate vice president of clinical affairs for Millennium Laboratories, a clinical diagnostic company that offers pharmacogenetic testing.
How It Works
Pharmacogenetic testing focuses mostly on variations in cytochrome P450 (CYP-450) enzymes, which are responsible for the metabolism of a host of drugs, including opioids, tricyclic antidepressants, benzodiazepines, selective serotonin reuptake inhibitors and methadone.1
“We look for SNPs, or DNA sequence variations that are seen in greater than 1% of the population, and for those known to exist in CYP 450 enzymes, especially in the CYP2D6 gene” said Tara Sander, scientific director of molecular diagnostics at Children’s Hospital of Wisconsin. CYP2D6 is one of the most important enzymes regulating the bioavailability and metabolism of drugs; at least 75 alleles of this gene exist that affect variance in drug metabolism.2 “We also look at drug transporters, like ABCB1.”
A SNP is an alteration of a single nucleotide in a genome sequence. It can cause a splicing defect, a frame shift, an amino acid change, or altered gene expression. Clinicians also look for copy-number variations (CNVs), which refer to an abnormal number of copies of a particular gene in a sequence.
“A CNV could lead to gene deletion or duplication. A deletion would mean you have half the gene expression you should, and fewer proteins,” Sander said. “If an individual has a SNP or CNV resulting in a protein with decreased or null function, this would reduce enzyme activity, which could indicate an intermediate or poor metabolizer.”
There are four types of drug metabolizers:
• Poor: Poor metabolizers have decreased levels of enzyme activity and process certain medications at a lower-than-normal rate.
• Intermediate: Intermediate metabolizers also activate and dispose of drugs more slowly, between an extensive and poor rate of metabolism.
• Extensive: Extensive metabolizers are considered “normal.” They are most likely to have the expected response to a drug.
• Ultra-rapid: Ultra-rapid metabolizers have high levels of enzyme activity and process drugs at a higher-than-normal rate. This could apply to someone with a CNV, as the duplicate genes would result in increased gene activity.
Results Guide Treatment
These categorizations mean different things depending on the type of drug taken. With a standard drug that is active when taken and oxidized and eliminated by metabolism, a poor metabolizer would be at risk for toxicity because he or she could not dispel the medication quickly enough. In the case of a “pro-drug,” or one that is inactive when taken and activated by metabolism, a poor metabolizer would be at risk for drug inefficacy.
After determining what type of metabolizer a patient is, doctors can adjust dosages or switch to a different drug type altogether to ensure the patient receives optimal treatment and avoid risks associated with toxicity or inefficacy.
“The test can be useful either before or during treatment,” Huskey said. “It’s up to the prescribing doctor to decide the timing of the test, depending on the situation.” Pharmacogenetic testing is most useful to monitor response to drugs with a narrow therapeutic window, which have a higher chance of causing adverse effects. Though not a pain medication, the anti-coagulant Warfarin offers a good example. With a narrow window and a potential side effect of severe, life-threatening bleeding, a predictive genetic test could greatly improve patient safety in this case.
According to Sander, the lab at the Children’s Hospital of Wisconsin also offers pharmacogenetic testing to the medical examiner’s office as an adjunct to medical history and autopsy reports.
Looking Forward
Pharmacogenetic testing “has become more convenient, more commercially available, and more reimbursable by third-party payers, thus helping to make it an important and available tool for clinicians,” Huskey said. But limitations exist.
For one thing, there is a lack of evidence supporting which metabolic enzymes are responsible for which drug responses. There may be as yet undiscovered enzymes playing a role in drug activation, oxidation and elimination. Additional large-scale prospective research is also needed to study the clinical outcomes of some pain medications.
Testing protocol also lacks standardization. If one lab analyzes the genes associated with a single drug class while another encompasses a wider range, their results will differ. ‘It’s important to know what platform was used and how comprehensive [the test] was,” Sander said. “Normal in one lab may not be normal for another lab.”
Since Millennium Labs announced the launch of its pharmacogenetic test (Millennium-PGT) at the 2012 PAINWeek conference, the technology has sparked an interest in the clinical community leaning toward personalized care and hints at further growth and development.
“Ten years from now, researchers could find new alleles,” Sander said. “It’s a dynamic field.”
Katie Siegel is on staff at ADVANCE.
References
1. Millenium PGT page. Millennium Laboratories. http://millenniumlabs.com/services/millennium-pgt-%E2%84%A0/
2. Kapil K, Jarmal G, and Mishra N. Drugs impact on CYP-450 enzyme family: A pharmacogenetical study of response variation. Indian J Hum Genet 2009 May-Aug; 15(2): 78-83. PMCID: PMC2910954
