Genetic Variation & Drug Response

Using genetic information to guide cardiovascular treatments

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A patient's personal tolerance to a handful of cardiovascular drugs no longer needs to be discovered after the medication has been prescribed and dosing has begun. Thanks to an upsurge of pharmacogenetic tests geared to target patients across the treatment spectrum, the cardiovascular market is benefitting from the potential for improved clinical outcomes and reductions in adverse events.

By definition, pharmacogenetic tests identify differences in metabolic pathways which can affect individual responses to drugs, both in terms of therapeutic impact and adverse effects. The information gathered in these tests can assist physicians with drug selection and dosing decisions.

Vanderbilt University School of Medicine launched PREDICT (Pharmacogenomic Resource for Enhanced Decisions in Care and Treatment) in 2010, a personalized medicine program designed to empower patients and doctors with genetic information. "Because each patient responds differently to the same drug, this genetic information helps doctors to reduce the risk of therapeutic failure or an adverse event," explained Josh F. Peterson, MD, MPH, assistant professor of biomedical informatics and medicine, Vanderbilt University School of Medicine in Nashville, Tenn.

The program's goals are threefold: to prospectively identify patients who are likely to receive target medications in the next 3 years; to genetically test these patients; and finally, to tailor their drug therapy according to the results.

Genetic Testing
At Vanderbilt University, DNA extracted from a patient's blood sample is genotyped for 184 common polymorphisms within 34 genes associated with drug absorption, distribution, metabolism and excretion using the Illumina Vera Code ADME Core Panel Assay. Some of the variants tested by Vanderbilt are currently part of research projects and not used clinically, however, as new drug-gene interactions are established, archived test results can later be added to patient records. PREDICT currently tests patients with a panel-based genotype test, however, the program aims to eventually offer a full sequencing test.

According to Peterson, the drugs that are potentially affected by proteins encoded by genes are wide ranging and cross many different disciplines within medicine. PREDICT has had a presence in the cardiovascular genetic market for about 3 years with great success in identifying genetic risks for common cardiovascular drugs, including the anti-platelet drug clopidogrel (Plavix) and the anti-coagulant warfarin.

Similarly, PDI, Inc. and Transgenomic, Inc. are partnering in the commercialization of CardioPredict, a broad-based genetic assay which identifies a patient's specific genes that influence the effectiveness and safety of many commonly used cardiovascular drugs. The CardioPredict Pharmacogenomic Optimization Panel is a buccal-based genetic test that enables personalization of treatment plans for patients receiving or being considered for common cardiovascular medications, such as antiplatelets, statins, antiarrhythmic, beta-blockers and anticoagulants.

"We know many patients seen by a cardiologist take more than one medication-one patient may be taking a statin, an anticoagulant and an antiplatelet," said Tom E. Callis, PhD, director of clinical genetics at Transgenomic. "Clinically actionable genetic variants should be considered when determining drug selection, dosing and monitoring."

Gathered from a simple buccal swab from the inside of a patient's mouth, CardioPredict analyzes 48 genetic markers in 10 genes to predict drug response. Both CardioPredict and Vanderbilt test for variations in the ABCB1 gene, which identifies patients at higher risk for poor outcomes while taking clopidogrel.

Personalized Medicine
"Our long-term goal is to personalize most of the treatments that we deliver," Peterson shared. "But that is highly dependent on further scientific discovery to produce high quality information about genetic and clinical risks that when accounted for in the prescribing process, improve therapeutic outcomes. We see a lot of therapeutic failures and adverse effects from medications-these drugs either may not work for a patient or cause harm. It simply makes sense to have a more precise route for tailoring prescriptions to optimize the patient's drug response."

Peterson indicated a parallel between the development of personalized medicine and the larger process of developing effective drug therapy. "There is a pipeline for development and implementation of pharmacogenes just like in drug development," he said. "A lot of what we currently have is in the early stage of development; drug-gene associations are being rapidly discovered and validated but what to do with the risk information is still an ongoing investigation."

Peterson emphasized that when implementing genetics in clinical practice and providing direct clinical decision support, other clinical considerations should be integrated with the genetic information. "We need to weigh all of the information available to us when evaluating a patient," he explained. "It may be genetics plus other patient attributes such as age, renal clearance and weight. The genetic information may not be sufficient to fully personalize the care."

But ultimately with pharmacogenomics, the prescribing is still in the hands of a clinician who will need to understand and act on genetic risks, Peterson told ADVANCE. "With next generation sequencing, the density of information is such that making genome-informed prescribing decisions will become much more complex and may become untenable without direct computational support."

According to Callis, CardioPredict and similar tests embody what personalized medicine is intended to do: customize healthcare for the patient. "These tests are tools that allow physicians to see the genetics and make decisions based on that information," he said.

Rebecca Knutsen is on staff at ADVANCE. Contact: rknutsen@advanceweb.com


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