Pharmacogenomics (PGx) is a field of medicine that studies the association between genetic variations and drug metabolism. PGx provides valuable insights into how individuals metabolize drugs, which can impact the effectiveness of medications and increase the risk of side effects. The adoption of PGx in clinical and diagnostic environments is gaining traction as knowledgebases and novel genetic insights continue to improve.

Drug Metabolism in The Body:

Pharmacogenetics is concerned with the study of the ways in which drugs are metabolized in the body. Some genes code for enzymes that metabolize drugs in the body, and genetic variations in these enzymes can affect the rate at which drugs are metabolized, impacting the effectiveness of medication and increasing the risk of side effects.

Some of the genes impacting drug metabolism are found in Table 1.

Table 1: Genes and their impact on drug metabolism

Additionally, genes can also code for proteins that transport drugs across cell membranes. Genetic variations in these proteins can affect the number of drugs that get into cells, which can impact medication effectiveness. Some genes code for receptors that drugs bind to in order to exert their effects. Genetic variations in these receptors can affect how drugs bind and interact with the body, which can impact medication effectiveness and the risk of side effects. 

Genes are also involved in inflammatory responses, which can affect how drugs act in the body. Moreover, genetic variations can also affect the development of tolerance to certain drugs, particularly in the case of opioids, alcohol, and some psychostimulants. Finally, some genetic variations can affect the way drugs interact with other drugs, food, or supplements, which can impact the effectiveness of medication and increase the risk of side effects.

Accuracy of Pharmacogenetic Tests:

Pharmacogenetic genetic tests are generally considered to be accurate, but the accuracy of a test can depend on several factors. Different pharmacogenetic tests have different levels of accuracy. Some tests are more accurate than others, and the accuracy of a test can depend on the specific genetic variant tested.

Healthcare providers should be familiar with the latest guidelines and the level of evidence behind the test they are ordering. Finally, it’s important to keep in mind that not all pharmacogenetics tests have been validated in large clinical studies, which means that the clinical utility of some tests may be uncertain.

Examples of Pharmacogenomics (PGx) Applications in Clinical Practice:

PGx testing can assist in identifying patients who are more likely to have adverse drug reactions. Some patients, for example, might carry a genetic change that impacts how they process the blood thinner warfarin, putting them at an increased risk of bleeding. PGx testing can assist in identifying these patients and lower their risk for negative reactions.

PGx testing is also able to direct drug selection, especially for patients who may not respond effectively to typical therapies. A patient suffering from depression, for example, may have tried a few selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine and sertraline but not responded effectively to any of them. A doctor may order PGx testing to identify genetic changes that could influence a patient’s response to antidepressants. The PGx test findings could indicate that the patient has a change in the CYP2D6 gene, which processes many SSRIs.

PGx testing can also aid in drug dosing optimization. A patient with elevated blood pressure, for example, may be prescribed amlodipine, a calcium channel blocker frequently utilized for managing high blood pressure. However, the patient’s blood pressure remains raised after several weeks of taking the drug at the standard dose. A physician may order PGx testing in order to identify genetic changes that could influence how amlodipine is processed in the patient’s body. The PGx test findings could indicate that the patient has a genetic change in CYP3A4, the enzyme responsible for amlodipine metabolism. Given this information, the patient’s amlodipine dose is adjusted.

The Value of Preventive Pharmacogenetic Testing:

Pre-emptive pharmacogenetic testing may offer helpful information about a person’s possible reaction to certain drugs, enabling medical professionals to make better-informed drug choices and dosing decisions. This can aid in avoiding potentially harmful reactions and improving outcomes for patients.

As an example, suppose a patient is scheduled for surgery and will need postoperative pain management. Pre-emptive pharmacogenetic testing is ordered by the medical professional to identify genetic changes that could influence the patient’s reaction to opioids such as codeine and oxycodone, which are frequently utilized for treating postoperative pain.

The findings of the pharmacogenetic test could indicate that the patient has a genetic change in the CYP2D6 gene, which impacts how the body metabolizes opioids. The patient may be a poor codeine metabolizer, which means they are unlikely to experience pain relief from the drug, or they may be an ultra-rapid oxycodone metabolizer, which increases the risk of overdose and other detrimental reactions.

Pharmacogenomics in Medication Discovery and Development:

Pharmacogenomics additionally has the potential to discover new drug targets, develop more efficient drugs, and decrease the risk of drug toxicity. Pharmacogenomics data can be used by geneticists and other researchers to discover genes involved in drug metabolism or transport and to develop novel medications that target these molecules.

An example of this may be a pharmaceutical company working on an innovative medication for managing depression. Researchers at the company use pharmacogenomics data to discover genes engaged in the metabolism of existing antidepressant drugs such as SSRIs.

The researchers discovered a genetic change in the serotonin transporter gene (SLC6A4) that is linked to a decreased response to SSRIs in some patients. This data will be used to create a new drug that will target a different aspect of the serotonin signaling pathway.

Furthermore, the researchers employ pharmacogenomics data to identify genetic changes linked to an elevated probability of SSRI-related side effects. The researchers are able to develop a medication with a reduced likelihood of these adverse reactions by incorporating this information.

Conclusion:

PGx has the potential to revolutionize the field of precision medicine. While pharmacogenetic genetic tests are generally considered to be accurate, the accuracy of a test can depend on several factors. Healthcare providers should be familiar with the latest guidelines and the level of evidence behind the test they are ordering.

Interpreting Pharmacogenomics with Geneyx 

The Geneyx PGx workflow offers comprehensive interpretations for 13 Clinical Pharmacogenomic Implementation Consortium (CPIC) level A/B and Pharmacogenomics Knowledge Base (PharmGKB) level 1/2 genes that affect the metabolism of 68 commonly prescribed drugs. A comparison between CPIC and PharmGKB evidence levels is shown in Table 2. This information is consolidated from multiple annotation sources, including CPIC, Food and Drug Administration (FDA), and the PharmGKB. For every gene reported, there are also useful hyperlinks to these databases, all of which are automatically pulled into the report.      

Table 2: PGx level of evidence according to Clinical Pharmacogenomic Implementation Consortium (CPIC) and the Pharmacogenomics Knowledge Base (PharmGKB)

Table 3: Commonly prescribed drugs and their PGx impact