Pharmacogenomics

Over 4 billion prescriptions are filled each year. Yet 50-75% of prescriptions don't work as intended

The solution is here in your DNA Genetic factors can account for up to 95% of drug-response variability and susceptibility. In other words, how a drug will or won't work for an individual.

Genomics delivers Precision

Adverse reactions to medications are a leading cause of hospitalizations and emergency room visits in the United States. As indicated in its name, pharmacogenomics (PGx) is the study of how genes influence the response to a particular drug.  Pharmacogenomics combines pharmacology; the study of drug absorption, metabolism, distribution and excretion (ADME) with modern advances in genetic research. With this shift toward personalized medicine, physicians are no longer using a "one size fits all model" to treat patients.  Until recently, many drugs adhered to a uniform prescription model and were prescribed or dosed regardless of genetic makeup.  Now with increased PGx testing it allows for a more personalized approach to pharmaceutical and therapeutic interventions.  Pharmacogenetics targets span a variety of different therapeutic areas including cardiology (warfarin), neurology / psychology (anti-depressants), respiratory (albuterol) and oncology (chemotherapy). 

Personalized medicine and pharmacogenomics

Pharmacogenomics holds the promise that drugs might one day be tailored to your genetic makeup. Modern medications save millions of lives a year. Yet any one medication might not work for you, even if it works for other people. Or it might cause severe side effects for you but not for someone else. Your age, lifestyle and health all influence your response to medications. But so do your genes. Pharmacogenomics is the study of how a person's unique genetic makeup (genome) influences his or her response to medications.

The most notable pharmacogenetics interactions are those with the CYP, SLC6A4 and HTR2A effector proteins.  The cytochrome P450 (CYP) genes encode for a family of enzymes that metabolize various therapeutics in order to detoxify the body.  These enzymes are most abundant within the liver, however they can be found in various tissues throughout the body.  Each specific gene encodes for one of the CYP450 enzymes, and variants within the CYP450 enzymes, which may result in polymorphisms.  These polymorphisms in turn reduce or inhibit the metabolic activity of the CYP450 enzymes.  Warfarin, a CYP2C9 and CYP34A inhibitor, and carbamazepine, CYP34A inducer, is one of the top 20 most commonly prescribed medications in the US that acts on both of these effector proteins.  Polymorphisms in these effector proteins can lead to a decreased efficacy of prescribed medication leading to serious complications and even fatality.  Approximately 40% of patients prescribed Warfarin exhibit a delayed effect of the medication due to these polymorphisms.  Warfarin is among the top three drugs exhibiting adverse events, accounting for 15% of drug related emergency and hospital visits.

While certain CYP mutations can lead to decreased drug efficacy like warfarin, other mutations can lead to drug toxicity.  CYP2D6 enzymes are also part of the cytochrome P450 family of enzymes and play a role in metabolism in a fifth of the drugs currently available.  CYP2D6 enzymes are found in SSRIs which make up a common class of antidepressants.  Individuals response to SSRIs vary based on their genetic makeup, individuals who poorly metabolize SSRIs are likely to have decreased efficacy to these antidepressants.  On the other hand, individuals who are characterized as ultrarapid metabolizers are likely to experience drug toxicity.  In either case, emergency care is typically required and can result in fatality.  While testing for these polymorphisms is not  a standard of care prior to prescribing these medications, testing is becoming more widespread with increased awareness. 

Canon BioMedical provides a broad collection of Research Use Only (RUO) PCR genotyping assays for pharmacogenomic research that enable scientists and clinicians to study how the human body metabolizes and responds to drug and therapeutic interventions.

What is personalized medicine?

Pharmacogenomics is part of a field called personalized medicine — also called individualized or precision medicine — that aims to customize health care, with decisions and treatments tailored to each individual patient in every way possible. Although genomic testing is still a relatively new development in drug treatment, this field is expanding. Currently, more than 100 drugs have label information regarding pharmacogenomics biomarkers — some measurable or identifiable segment of genetic information that can be used to direct the use of a drug.

Why is genomic information helpful?

Each gene provides the blueprint for the production of a certain protein in the body. A particular protein may have an important role in drug treatment for one of several reasons, including the following:

  • The protein plays a role in breaking down the drug.
  • It helps with the absorption or transport of the drug.
  • The protein is the actual target of the drug.
  • It has some role in a series of molecular events triggered by the drug.

When researchers compare the genomes of people taking the same drug, they may discover that a set of people who share a certain genetic variation also share a common treatment response, such as:

  • A greater risk of side effects
  • Severe side effects at relatively low doses
  • The need for a higher dose to achieve a therapeutic effect
  • No benefit from the treatment
  • A greater or more likely benefit from the treatment
  • The optimal duration of treatment

This kind of treatment information is currently used to improve the selection and dosage of drugs to treat a wide range of conditions, including cardiovascular disease, lung disease, HIV infection, cancer, arthritis, high cholesterol and depression.

In cancer treatments, there are two genomes that may influence prescribing decisions — the genome of the person with cancer and the genome of the cancerous (malignant) tumor. There are many causes of cancer, but most cancers are associated with damaged DNA that allows cells to grow unchecked. The "incorrect" genetic material of the unchecked growth — the malignant tumor — is really a separate genome that may provide clues for treatment. For example, the drug trastuzumab (Herceptin) is most likely to be effective against breast cancer cells that have an extra copy of a particular gene and high levels of the gene's corresponding protein.

How does pharmacogenomics work in practice?

An example of pharmacogenomics in treatment decisions is the use of a blood-thinning drug called warfarin (Coumadin, Jantoven). If you have a blood clot, your treatment may include a prescription for warfarin to treat the current clot and to prevent additional blood clots from forming. Your doctor's goal is to prescribe a dose that will be strong enough to prevent blood clotting but not strong enough to cause adverse reactions, such as internal bleeding (hemorrhaging). The window for the effective and safe dose of this drug for any person is relatively narrow. Dosage has traditionally been based on such factors as weight, age, and kidney and liver function, as well as a laboratory test to assess the blood-thinning effect of the drug in each person. The dosing guidelines, although valuable, may have limited value in predicting the outcome for every person.

In the early 2000s, studies comparing treatment outcomes with genomic data revealed that genetic variation was associated with either an increased risk of hemorrhaging or with the need for a higher dose to be effective.

Because of these findings, your doctor may use your genomic information to help guide treatment decisions. A tissue sample swabbed from inside your cheek or a blood sample provides cells for a laboratory test to decipher your genome. Based on the results, your doctor may judge more accurately what dose of warfarin is likely to be safe and effective for you or whether warfarin is even an appropriate treatment option.

The future of pharmacogenomics

Although pharmacogenomics has much promise and has made important strides in recent years, it's still in its early stages. Clinical trials are needed not only to identify links between genes and treatment outcomes but also to confirm initial findings, clarify the meaning of these associations and translate them into prescribing guidelines. Nonetheless, progress in this field points toward a time when pharmacogenomics may be part of routine medical care.