3. Describe how variants in the CYP2C19 gene impact Plavix metabolism. 4. Compare molecular genetic technologies for pharmacogenomics testing

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1 UP! UNDERSTANDING PHARMACOGENOMICS (PGX) Robert Pyatt Ph.D., Director Sanford Medical Genetics and Genomics Laboratories and Associate Professor, Dept of Internal Medicine, University of South Dakota April Schultz Pharm D, Manager -Pharmacogenetics, Sanford Imagenetics OBJECTIVES: 1. Define pharmacogenomics (Pgx) including pharmacodynamics and pharmacokinetics 2. Explain the utility of TPMT testing in pediatric acute lymphocytic leukemia (ALL) 3. Describe how variants in the CYP2C19 gene impact Plavix metabolism 4. Compare molecular genetic technologies for pharmacogenomics testing SCIENCE OF MEDICATIONS WHAT IS PHARMACOGENOMICS? + STUDY OF GENES AND THEIR FUNCTIONS PHARMACOLOGY TAKING INTO CONSIDERATION HOW GENETIC FACTORS EFFECT A PATIENTS REACTIONS TO MEDICATIONS *The study of medication response in relation to the genome Pharmacogenomics Pharmacogenetic Biomarkers *Alleles coding for a gene that influences medication effectiveness and toxicity *Further classified -pharmacodynamics -pharmacokinetics Pharmacodynamics (PD) What a drug does to the body Mechanism of action biochemical interaction of a drug to produce it s pharmacological effect Desired effects = efficacy Side effects = toxicity Receptor binding protein binding Signal transduction control cell growth, proliferation and metabolism 1

2 EFFICACY *decrease itching *decrease sneezing *decrease runny nose Pharmacodynamics of Antihistamines SIDE EFFECTS *sedation *dry mouth *dry eyes Pharmacokinetics (Pk) What the body does to the drug Absorption Distribution Metabolism Elimination IN OUT Pharmacokinetics and Pharmacogenomics DO PD AND PK HAVE ANY CONNECTION TO PGX? Genetic variants -> metabolism change PGx YES!!! ACTIVE DRUGS - BIOLOGICALLY ACTIVE PRODRUGS BIOLOGICALLY INACTIVE DRUG Absorbed thru GI tract Distributed in the blood Broken down by liver enzymes Excreted by the kidneys Require biological activation Improve drug delivery or specificity Improve bioavailability Decrease toxicity Cytochrome P450 enzymes (CYP2C19, CYP2D6, etc.) Genetic variants in CYP enzymes Ex. Codeine > Morphine 2

3 Over 50% of drugs are metabolized by: CYP3A4, CYP1A2, CYP2C9, CYP2C19, and CYP2D6 which are highly polymorphic Pharmacogenomic Enzyme Variants Genetics variants in metabolizing enzymes and drug transporters that cause changes in drug metabolism: Insertions, Deletions, Inversions, Translocation Assignment of phenotype and functional affect: Ultra-rapid metabolizer (UM)= Lack of therapeutic response, responds to increased dose Extensive (normal) metabolizer (EM) = Expected therapeutic response, responds to normal dosage Intermediate Metabolizer (IM) = Exaggerated therapeutic response, responds to reduced dosage Poor metabolizer (PM) = Adverse effects, responds to alternative medication COMMITMENT TO BETTER PATIENT CARE SANFORD GUIDELINES FOLLOW CPIC Healthcare professionals (MD, PhD, Pharm.D.) International Consortium to facilitate the use of Pgx tests for patient care Provide guidelines for actionable prescribing decisions from genetic test translation Create clinical practice guidelines based on peer reviewed, evidence based, updatable information Standardized format for terminology, evidence grading and clinical recommendations Published in Clinical Pharmacology and Therapeutics Dutch Pharmacogenetics Working Group and European Pharmacogenetics Implementation Consortium CPIC MAPPING OF DATA Enter Text Here CYP2C19 *2/*2 PM Poor Metabolizer CYP2C19 *2/*3 PM Poor Metabolizer CYP2C19 *2/*4 PM Poor Metabolizer CYP2C19 *2/*5 PM Poor Metabolizer CYP2C19 *2/*6 PM Poor Metabolizer CYP2C19 *2/*7 PM Poor Metabolizer CYP2C19 *2/*8 PM Poor Metabolizer 3

4 CREATING GUIDELINES Enter Text Here GENETIC TESTING AND PHARMACOGENOMICS AT SANFORD HEALTH Preemptive testing Reactive testing Pharmacogenomic testing for 8 genes now - 11 genes soon CYP2C19 CYP2D6 CYP3A5 CYP2C9 VKORC1 SLCO1B1 TPMT DPYD CYP4F2 UGT1A1 IFNL3 PROCESS AND REPORTING REPORTING/DECISION SUPPORT FOR PRESENT Ordered entered into Electronic Medical Record Blood drawn and sent to molecular lab for testing Genotyping results validated by lab director(s) Phenotyping/functional status validated by pharmacist(s) Patient chart review DECISION SUPPORT FOR FUTURE THIOPURINE METHYLTRANSFERASE (TPMT) Lab results/reports available in EMR Best Practice Alerts (BPA s) built and programmed to fire for providers as appropriate TPMT activity inherited as monogenic co-dominant trait TPMT is responsible for the inactivation of Thiopurines - all prodrugs 6 Mercaptopurine, Azathioprine, and Thioguanine Normal function = *1 Non function alleles = *2, *3A, *3B, *3C, and *4 1 or 2 variant alleles cause increased concentrations of active drug and life threatening myelosuppression 4

5 PATIENT CASE #1 PATIENT CASE #1 3 yo male Parent describe symptoms: fever, loss of appetite, fatigue, and bruises that don t seem to heal Blood tests suspect Acute Lymphocytic Leukemia bone marrow aspirate/biopsy confirm diagnosis Chemotherapy ASAP 6-MP will be used for Intensification phase MD orders TPMT pgx to ensure proper dosing of 6-MP Patient results as *1/*3A = intermediate activity 6-MP dose decreased by 30% Patient returns with moderate myelosuppression Dose decrease another 20% Patient tolerates new dosing well and is able to progress treatment to maintenance phase CYP2C19 PATIENT CASE #2 CYP2C19 = liver enzyme, polymorphic, responsible for metabolism for several medications (Plavix, SSRI s, TCA s, etc) CYP2C19 is responsible for the conversion of clopidogrel (prodrug) to its active metabolite Normal function = *1 Non function alleles = *2 rs , *3-*8 Increased activity = *17 1 or 2 non-function alleles results in decreased or no platelet inhibition 73 yo diabetic female Arrives via ambulance with sudden onset of shortness of breath, nausea, and pain in the jaw Troponin elevated ST segment deviation on EKG Cath lab for percutaneous coronary intervention stents placed Patient requires antiplatelet therapy to decrease stent thrombosis - Plavix PATIENT CASE #2 MD orders Plavix 75 mg po daily and a CYP2C19 2 days later -> Pgx result *2/*3 = poor metabolizer Call made to patient change to Brilinta 90 mg po bid Turnaround time -> Major Adverse Cardiovascular Events (MACE) 5

6 CYP2D6 AND CYP2C19 CYP2D6 = liver enzyme, polymorphic, responsible for metabolism for several medications (SSRI s, TCA s, codeine, etc.) CYP2D6 and CYP2C19 responsible for metabolism of SSRI s and TCA s Normal function = *1, *2 Decreased function = *9,*10,*41 Non function alleles = *3-*6 Copy number = *5 (deletion) xn (duplication/multiplication) Drug-gene variants can cause therapeutic failure or increase in adverse effects PATIENT CASE #3 12 yo female with history of major depression, anxiety, insomnia, decreased appetite, abdominal pain, and suicidal ideation 2 admissions to behavioral health institution Counselor biweekly, stops eating (lost 5 pounds = 5% BM) and sleeping, missing school, crys continuously and states I don t want to do this anymore Increased feelings of helplessness and guilt, parent-child relationship issues Sent text to a friend stating that she was hoping she would have died overnight Prozac 20 mg>prozac 30 mg>wellbutrin XL>Topamax Prozac and Topamax d/c d due to side effects Wellbutrin XL not seeing much benefit Basic pharmacogenomics panel 2/9/18 CYP2D6: *4/*4 = poor metabolizer CYP2C19: *1/*1 normal metabolizer PATIENT CASE #3 Basic pharmacogenomics panel 2/9/18 CYP2D6: *4/*4 = poor metabolizer CYP2C19: *1/*1 normal metabolizer Per CPIC guidelines: avoid TCA s, Luvox and Paxil. Avoid Prozac due to previous side effects Consider Lexapro, Celexa or Zoloft > Lexapro 10 mg po daily started Patient update (4 weeks after Lexapro): significant improvement in depression, anxiety improved slightly, no thoughts of suicide, increased interest in activities, work caught up in school, sleeping better, abdominal pan resolved PATIENT CASE #3 ADDITIONAL INFO Pediatric patients caveats Very few guidelines/studies Chemo agents Chemo rescue Supportive meds Reactive testing instead of preemptive Enzyme maturation extrapolate results depending on gene THANK-YOU! QUESTIONS? 6