PHARMACOGENOMI CS TESTING:
What, Why, Who and When
Kyle John, MD
2024 GCMS Conference
Breckenridge, CO
7/17/24 8:00-9:00
Disclosure s
Speaker - Myriad Genetics
Objectives
• To be able to explain what pharmacogenomic testing entails
• To become familiar with why pharmacogenomic testing could be utilized
• To learn who may benefit from pharmacogenomic testing
• To be able to describe when pharmacogenomic testing should be employed
What is PGX Testing?
• Humans have two copies of every gene, one from each parent
• Alleles are slight variations of a gene; they may be identical or differ in number and function
• Genes are made of DNA
• Some DNA codes for mRNA
• mRNA codes for proteins
• Proteins do many important tasks in our bodies
What is PGX Testing?
• Medication efficacy can be influenced by two primary genetic factors, pharmacokinetic and pharmacodynamic
• Kinetic refers to the genes that code for the main CYP450 liver enzymes responsible for medication metabolism
• Dynamic refers to the genes that code for the ability to transport a neurotransmitter, like Serotonin
What is PGX Testing ?
CYP450 Enzymes
2D6
3A4
3A5
2C9
2C19
1A2
2B6
UGT2B15
CES1A1
What is PGX Testing?
Patients may have too few, too many, or the normal number of/functional alleles for a particular CYP450 enzyme
• Poor metabolizer
• Intermediate metabolizer
• Normal metabolizer
• Rapid metabolizer
• Ultrarapid metabolizer
What is PGX Testing?
Patients may also have drugdrug-gene interactions:
• Strong CYP2D6 inhibitors: fluoxetine, paroxetine, bupropion
• Moderate/weak CYP2D6 inhibitors: duloxetine, sertraline, escitalopram
• CYP3A4 inducers: carbamazepine, phenobarbital, phenytoin, St. John’s wort
• CYP3A4 inhibitors: fluoxetine, fluvoxamine, grapefruit juice, CBD
• CYP2C19 inhibitors/substrates: THC, CBD, PPIs, oral contraceptives
What is PGX Testing?
• Four leading global agencies have the most research regarding PGX testing and best-practice recommendations
• There are common recommendations, but…
• They don’t always agree
Why Order PGX Testing?
• Increase medication success • Reduce adverse drug reactions • Decrease healthcare cost • Improve healthcare quality
Who Should be PGX Tested?
• History of medication
failure
or intolerance
• Family history of medication failure or intolerance
• Increased ethnic risk
• High risk diagnostic groups
When Should PGX be Ordered ?
• Before beginning treatment
• During treatment if the patient is not finding maximal benefit or is experiencing significant medication intolerance
• After multiple failed trials
When Should PGX be Ordered
?
Thoughtful Use of PGX Testing
1. Make an accurate diagnosis
2. Determine if medication is indicated
3. Check PGX results if available, or discuss with the patient/family the potential benefits of obtaining
4. Choose a medicine based upon:
1. Best-practice guidelines
2. FDA recommendation(PI)
3. Family history/past trials
4. Side effect avoidance
5. Adjust the dose or consider alternatives based on PGX results
Companie s Who Test
Comprehens ive Results For Example…
Research Supported
What is PGX testing?
1. How we clone someone’s DNA
Quiz Question #1
2. How we test for Down’s Syndrome
3. A way to determine if patients have kinetic or dynamic genetic variations affecting medication metabolism and efficacy
4. How the PGA prevents professional golfers from juicing before tournaments
Quiz Question #2
PGX testing should be used to?
1. Determine how a patient might respond to a particular medication
2. Pick the “can’t fail” medication to treat depression
3. Know which patients will respond to therapy vs. medication
4. Rule out substance use as the cause for a psychiatric illness like depression or anxiety
Quiz Question #3
Which patients would most benefit from PGX testing?
1. Only female patients should be tested
2. Only patients who fail 3 drug trials should be considered
3. Any patient can be tested, but they must be wealthy to afford the cost
4. Any patient can be tested
Quiz Question #4
PGX testing should be used when?
1. Before taking a thorough history
2. After a patient has failed multiple medication trials and been hospitalized 3. Any time you consider medication management for a psychiatric disorder
4. On the first and third Tuesdays of the month, if there is a full moon
Thanks for Attending!
References
• Strawn, JR. NEI Congress, 2022.
• Ramsey LB et al. AnnuRev PharmacolToxicol2020;60:311-31.
• Ramsey LB et al. J Am AcadChild AdolescPsychiatry 2021;60(6):660-4.
• GeneSight.com
• Clinical Pharmacogenomics Implementation Consortium (CPIC) https://cpicpgx.org/guidelines/
• Dutch Pharmacogenetics Working Group https://www.knmp.nl/
• Pharmacogenomics Knowledge Base (PharmGKB) https://www.pharmgkb.org/
• https://doi.org/10.1016/j.psychres.2023.115102