Joseph McGraw PharmD MPH PhD Associate Professor of Pharmaceutical Sciences CUW School of Pharmacy President and Chief Scientific Officer Persotype DX LLC Background PhDBiopharmaceutical Sciences ID: 1046407
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1. HepSight: A Personalized Medicine Tool for Drug Selection and DosingJoseph McGraw, Pharm.D., M.P.H., Ph.D.Associate Professor of Pharmaceutical Sciences CUW School of Pharmacy President and Chief Scientific Officer Persotype DX LLC
2. BackgroundPh.D.-Biopharmaceutical SciencesPharmacokinetics/ Pharmacodynamics/ Toxicology PathwayDoctoral work: Adverse Birth Outcomes in Pregnant African American Women Exposed to Organohalogens via Great Lakes FishM.P.H.Pharm.D.B.S. Chemistry
3. Phenotypeshttps://www.ncss.com/software/ncss/ncss-plots-and-graphs/
4. PhenotypesGeneticsEnvironmentPKPDDrug Dose & SelectionResponsePhenotypePHARMACOTHERAPY RESPONSE
5. Drug Exposurehttps://www.boomer.org/c/p4/c15/c1504.html
6. CYP 450 ISOENZYMESFamily of oxidative enzymes Metabolize 75% of drugs Major determinant of drug clearance!!!!!!!!!!!Constitutively expressed and inducedCYP 1A2, 2C9, 2C19, 2D6, and 3A4/5 Account for ~90% of CYP450 drug metabolismCYP3A4/5 metabolize ~40-50% of drugs
7. Adverse Drug ReactionsADRs:Cost = $500 Billion/year90.3% from therapeutic doses of drugs properly administered in hospital 1/5 injuries or deaths per hospitalized patientRates doubling every 5 years since 2000Variable metabolism identified as a major causeCytochrome P450 enzyme isoforms
8. PROBLEMSADRs more likely amongst variant metabolic phenotypesHealth disparities exist amongst ADRsLack of diversity in drug clinical trialsSolution: Phenotype on an individual basis to avoid ADRs and Disparitieshttps://www.fda.gov/downloads/Drugs/InformationOnDrugs/UCM570195.pdf
9. A Note on Phenotyping“The generation of genomic data will have little value without corresponding phenotypic information”— J. Craig Venter, PhD
10. Personalized MedicineProblems with Genotype Predicted PhenotypeRegulatory controls of gene expression TRXN, XLTN, post-transcriptional controlsEpigeneticsMultigenic responseEnvironmental factors Concomitant disease(s) Drug therapy Dietary/lifestyle habits Genotyping predicts categorical outcomeUltra-rapid, extensive, intermediate, or poor metabolizer
11. CYP450 Activity Variability01,0002D6040-503A4/5021-282C19040-1301A2What are your enzyme activity levels?
12. CYP450 CharacteristicsCYP450 ISOFORMTOTAL LIVER CONTENT (%)% DRUGS METABOLIZEDACTIVITY VARIABILITY (Fold)1A28-131040-1302C194-135-1321-282D61-215-25>1,0003A420-5036-5040-503A50.2-2Expected similar to 3A4Not reported2C910-2010-203-27
13. CYP450 Drug MetabolismClopidogrel3A4 3A51A22D62C19TacrolimusTamoxifenPsychotropics
14. PROBEDOSE (mg)CYP450 ISOFORMMETABOLITECaffeine1001A2ParaxanthineOmeprazole402C195-HydroxyomeprazoleDextromethorphan HBr302D6DextrorphanEplerenone253A4 6-β-Hydroxyeplerenone 3A4/521-Hydroxyeplerenone HepSight
15. Phenotype MeasurementMetabolic Phenotype:CYP1A2, 2D6, 2C19, 3A4/5
16. n= 90Unpublished McGraw et al.CYP 2D6 Metabolic Phenotype(Healthy Adults)
17. CYP 450RecommendedClinical Substrate Probes1A2caffeine2C9warfarin2C19omeprazole2D6dextromethorphan3A4Midazolam???Recommended CYP450 Substrate Probes Adapted from Zhou et al. 2004 3A43A4/5Ideal Probe: Safe, Specific, Easily Assessed
18. Unpublished McGraw et al.~50 foldvariability~200 foldvariabilitySimCYP Modeled Data - CYP3A4/5
19. Customer QuotesHepsight: “I need that for validation and identifying unidentified phenotypes”Pharmacogenomic researcher and data provider for major medical centerGenotyping: “Genotyping gives a predicted phenotype…genes don’t change but phenotypes do”Clinical Pharmacogenomic service provider Northshore HealthcareHepsight: “I could definitely use that in my practice”, “It could validate my recommendations”Independent entrepreneur pharmacist, pharmacy resident
20. MARKET PATH
21. MARKET COMPARISONNon-Invasive SamplingSpeed (day)Real-time AccuracyQuantitative ResultCYP3A4Activity
22. ATTRIBUTES AND ATTITUDESPersistenceRespectGratitudePracticality
23. THANKS!Thanks:Dr. Katie BichlerDr. Dan SemDr. Ernie Stremski Dr. James LokkenMirielle Nauman Dr. Steven ScholzenDr. Mitchell Cherney Dr. Kellen DorffDr. Adam Koopmann Abigail McGrawRevathi KodaliMichael HoefsJacob Switzer