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09:35 AM

Pharmacogenetics: Advancing Personalized Medicine through Individualized Drug Therapy

Andrea Gaedigk, PhD, Director of the Pharmacogenetics Core Laboratory at Children’s Mercy Hospital Kansas City and the PI of the PharmVar Consortium, a central repository for pharmacogene (PGx) variation that focuses on haplotype structure and allelic variation, and Neil Miller, Director of Bioinformatics of the Center for Pediatric Genomic Medicine at Children’s Mercy Hospital Kansas City

Pharmacogenetics is increasingly utilized to advance individualized drug therapy as the health care industry shifts to value-based care. Not every patient responds to medications the same way and genetic factors can help determine how a person metabolizes drugs, and why a drug may or may not work.

There have been huge advances made in DNA testing to guide drug choice and dosage in children and adults, and it’s this individualized approach of treatment, instead of the one-size-fits all model, which will position pharmacogenetics and genomics at the leading edge of precision medicine.

Evolution of Drug Metabolism: The Animal Plant Warfare

To help understand why individuals respond to drugs differently, one needs to look at how drug-metabolizing enzymes have evolved over time, specifically those encoded by the cytochrome P450 (CYP 450) supergene family. P450 enzymes are noted for their high degree of inter-species and inter-individual variability, which has been attributed to animal plant warfare.

Certain plants produce toxins that prevent animals from eating them. In return, animals and humans developed defense mechanisms including CYP enzymes that allow their bodies to metabolize and get rid of potentially harmful chemicals, so they can ingest the plants. Many CYP enzymes can metabolize many drugs and a given drug is often metabolized by more than CYP. This redundancy helps protect animals and humans from toxins in plants and other environmental chemicals.

The vast majority of drugs are not natural products, but many are derivatives from substances originally found in plants or other organisms. This is why a lot of these enzymes that have evolved to protect us from everything we're exposed to could also be the enzymes that metabolize many of the drugs available today.

Given this evolution, it is easy to understand why individuals have genetic outfits that translate into a wide range of activity: some people have no or low enzyme activity of a particular CYP enzyme while others are at the opposite end and have very high activity; for other CYPs, a person might just have the reverse or what is considered normal activity. Depending on the environment, one or the other might be better suited to survive. So depending on a patient’s genetic make-up, s/he may respond well to a drug or not at all or even experience side effects.

Individualized Approach to Drug Dosing

Drugs and dose recommendations are developed for the average person, but what if you’re not the average person? There are many case reports describing patients who tried different drugs year-after-year but never found a therapy that worked for them. It wasn’t until pharmacogenetic testing was finally done and it turned out they were, for example, an ultra-rapid metabolizer, meaning they had an extra functional gene copy that made them metabolize the drug extremely fast. Or, on the opposite end, both of their gene copies had variations that renders them non-functional making them a poor metabolizer.

It is mostly patients with these extreme metabolizer phenotypes that benefit from drug dosing that is different than usual. Giving an ultrarapid metabolizer the standard dose of a medication often doesn’t work since their bodies metabolize and clear the drug too quickly, and they never reach the level of exposure required for the drug to be effective. One solution may be to increase drug dosage, which you would never do for the average person, or switch to a medication from a different drug class that utilizes a different pathway. For a poor metabolizer, the dosage may need to be decreased since the exposure to the drug will be too high as the body metabolizes the drug slower than usual.

Another good example where being a poor or ultrarapid metabolizer may have a significant impact is with the pain medication codeine. Codeine is in itself a drug that is not active, but instead needs to be bio-activated into a morphine derivative. If the body is a poor metabolizer and can’t form the morphine component, the patient may not get the desired pain relief. On the other extreme, if the person is an ultrarapid metabolizer the morphine metabolite may reach dangerously high levels that have been reported to be deadly.

Taken together with all the variability in drug metabolism, it can be challenging to find the right dose, for the right drug in both adults and children. As we learn more about the genes that contribute to drug metabolism and drug transport and how their variants effect their function, we improve our ability to predict what a drug response will be in the individual patient.

The ultimate goal is to really take out the guess work. By taking a patient’s history, their ethnic background, the family history and genetics into account, we hope to find better starting points for drug therapy.

Preemptive Genetic Testing

Would there be benefit to doing preemptive genetic testing early in a person’s life, so the information is available when needed later on? Unlike a lot of medical tests, genomic testing can be relevant for an individual’s entire life. For instance, if a physician has a newborn’s pharmacogenetic profile on record, when that child comes back as a teenager they can use that information to help prescribe the most effective drug for that particular patient.

Currently, pharmacogenetic testing is often done in retrospect, for example when a drug doesn’t work or the patient experiences side effects. We see many kids in our GOLDILOKS clinic that have tried a long list of drugs without success as well having experienced side effects such as weight gain, poor sleep, or drowsiness, to name a few. Pharmacogenetic testing can help prevent putting patients through this trial and error and avoid wasting time on something that’s never going to work.

Sharing Actionable Data

Given the wide range of genetic variation in the genes that contribute to how the body processes a drug, it’s important as an industry that we all speak the same language and use the same definitions when referring to genetic variants. Many health care professionals have not learned about pharmacogenetics in their training and may therefore not utilize such testing in their own practice. Increasingly, pharmacogenetic data are available to patients through direct-to-consumer testing, meaning that patients walk into their doctor’s office with their own pharmacologic genetic results. While the test results can be informative, they can also be overwhelming and a physician may not know what to do with them. To help health care professionals interpret pharmacogenetic tests, the Clinical Pharmacogenetics Implementation Consortium (CPIC) has published guidelines for many gene-drug pairs. Guidelines such as these help physicians determine the best course of treatment based on the patient’s genetic makeup.

In addition to standardizing definitions, it’s also important to have a single place to keep track of genetic variation and encourage stakeholders to share their data. Right now, data is sitting in silos in hospitals and data centers around the world and we need to get the information into a centralized repository so that everyone can make use of it. Our hope is that the new Pharmacogene Variation Consortium (PharmVar) database will serve as a global resource for both standardization and data sharing.

Pharmacogenetics is clearly not the only answer for making drug prescription more effective, but it can be an important piece of a larger strategy to move individualized drug therapy forward. Genomic approaches are here to stay and will be the next frontier for improving patient outcomes in everyday health care.


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