“Pharmacogenomics and Dosing”

erence to determine if a gene test should be considered before administering that drug. - https://cpicpgx.org/genes-drugs/. Just key in the generic name of a medication, and if the CPIC level is A or B or the FDA label says a pharmacogenomics test is required or recommended, testing is advisable. If two genes are implicated for prescribed medications or medications under consideration, Medicare will cover the panel in full.

“Pharmacogenomics and Dosing” (Kristine Ashcraft) [#25] Unfortunately, guidelines and reimbursement policies do not align with current evidence. They're outdated. Awareness of these specific drug-gene interactions should be widespread and tested for. This is something that can be done once in a lifetime.

Although there aren’t many cancer medications that have drug-gene guidance, a lot of the other medications that cancer patients need are impacted by pharmacogenomics and should be considered.

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“Pharmacogenomics and Dosing” (Kristine Ashcraft) [#25] Meeting Notes Prostate Cancer Lab Meeting - Pharmacogenomics and Dosing (Kristine Ashcraft) Wed, 9/14 • 45:20 SUMMARY KEYWORDS patient, medications, drug, gene, dose, pharmacogenomics, testing, question, impact, interactions, metabolizer, poor metabolizer, ultra rapid, evidence, drug metabolizing, guidelines, cytochrome, pharmacogenetics, cancer, prostate cancer SPEAKERS Kristine Aschcraft, Marty Tenenbaum, Ally Perlina, Brian McCloskey, Rick Stanton, Brad Power Brian McCloskey 00:06 Kristine Ashcraft is with us today from Invitae, and she is going to be talking about pharmacogenomics.

“Pharmacogenomics and Dosing” (Kristine Ashcraft) [#25] growing list of medications, whether we need a higher dose, a lower dose, or a different medication altogether. In terms of the problem this helps us address, non-optimized medications are a major public health problem. We lose a life every two minutes in the United States due to non-optimized medications.

s are a major public health problem. We lose a life every two minutes in the United States due to non-optimized medications. In 2016, the last time it was measured, we spent $528 billion nationally on non- optimized medications, which is more than we spent on the drugs themselves or on any major chronic disease, including cancer.

Regarding cancer care, greater than 99% of patients will have a pharmacogenetic variation that impacts their response to on average more than 10 commonly prescribed medications. And the more medications you're taking, the more likely you are to have a problem.

Although this may not impact a prostate cancer medication per se, it can impact the overall medication regimen and have an impact on the overall health of a patient.

“Pharmacogenomics and Dosing” (Kristine Ashcraft) [#25] About half of the medications that are prescribed to patients do not work as intended, ranging from about 38% of antidepressants, up to three-quarters of cancer medications. Genetic variability is not the only thing at a play here, but it is a major contributor to treatment failure.

There's a very interesting analysis that came out of the UK last year.

“Pharmacogenomics and Dosing” (Kristine Ashcraft) [#25] have an atypical response to at least one medication, but on average 10 drugs.

The other thing that was interesting, they have longitudinal data in primary care of the medications that were prescribed for these patients over time, and they found that one in five new prescriptions in primary care was impacted by pharmacogenomics, and one in 11 would have specific drug or dose change guidance associated with them.

This is a snapshot of some, and not all, of the medications that are impacted by high evidence drug/gene interactions, meaning that if testing is done, there is specific guidance if a variation is found on how you would consider modifying the drug or dose selection based on that information. I bolded the medications that I think you may come across in prostate cancer care.

I know statins sometimes are utilized. They're certainly pain management, some antiemetics. But the thing to keep in mind over here on the right in the pie chart, is that the same genes impact drug response across all sorts of different clinical areas for life.

I think of pharmacogenetic profiling as something like a seatbelt for medication management that really needs to be used every time a medication decision is made the rest of the patient's life to understand if they need different archetypes.

“Pharmacogenomics and Dosing” (Kristine Ashcraft) [#25] We're working on a study about the impact in cancer care right now, but these are broader. I'm just showing that this can be very helpful for patient care. This was a study that was done in

o understand if they need different archetypes.

“Pharmacogenomics and Dosing” (Kristine Ashcraft) [#25] We're working on a study about the impact in cancer care right now, but these are broader. I'm just showing that this can be very helpful for patient care.

This was a study that was done in patients 65 and older, taking at least three medications, one of which was known to have high evidence drug/gene interactions at minimum and what was seen in just four months. 71% fewer emergency department visits. 39% fewer hospitalizations. Saving $1132 per patient prior to the cost of testing.

“Pharmacogenomics and Dosing” (Kristine Ashcraft) [#25] Here's a follow up study. This was done in patients that were flagged as being at high risk of readmission. This was a program that was already doing an exceptionally good job. They were in the top 10th percentile for lowest readmission rates in the country.

That's because they had a very proactive program, where a pharmacist would visit the patients in the home and review their medications because medication-related issues are one of the main reasons patients end up back in the hospital.

These pharmacists were either randomized to give the patient's treatment as usual or high touch pharmacy care where they were given access to pharmacogenetic testing and improved clinical decision support that didn't just look at drug/drug, but also drug/gene interactions and cumulative interaction risks.

What was seen in just 60 days was 42% fewer emergency department visits and 52% fewer readmissions. It was not an endpoint of the study, but 85% fewer deaths, saving $4380 to a patient in just two months. Kristine Aschcraft 06:05 Here's a quick lesson in pharmacogenetics.

Generally, when we do testing, we're looking at these drug metabolizing enzymes, mainly cytochromes, that mainly express in the liver. We place people into different categories or phenotypes, based on the genetic information. Generally, when we prescribe medications, we assume all patients are normal metabolizers, also called “extensive metabolizers” in the literature.

I think of this like a two-lane highway. You take medications, and they must go through these enzymes to be converted to something the body can then flush out and get rid of. Your normal metabolizer has two lanes of this highway that processes medications. You have intermediate metabolizers with one active and one inactive gene, or down to one lane of this highway.

Poor metabolizers have no, or very, very reduced activity, or no lanes. The ultra-rapid metabolizers have duplications or upregulation, or additional lanes of these drug metabolizing highways.

“Pharmacogenomics and Dosing” (Kristine Ashcraft) [#25] Here's the difference between active drugs and prodrugs. We take most medications in an active form. They often hit the cytochromes or sips in the liver, these drug metabolizing highways, to be converted to something we then flush out and get rid of.