Big Data Course Week 7 Test2Learn TM 5/7/16

Transcription

1 The site is Usernames are first letter of first-name + first 3 letters of last name (i.e. John Smith would be jsmi ) Passwords are the same as the usernames. Everyone will need to accept the terms of use, after which they will be prompted to change their password Either connect your account to 23andMe or use an anonymous real genetic dataset 1

2 Phenotyping prediction: tasting exercise 1931 Arthur Fox discovery of variance in taste perception of phenylthiocarbamide (PTC) PTC is a chemical similar to bitter chemicals in vegetables, coffee, dark beers. Some people are unable to taste it ( taste blind or nontasters). Let s repeat his experiment using PTC impregnated paper and share our data Fox, AL. Proc. Natl. Acad. Sci. USA : Identify your patient s TAS2R38 genotype and predicted phenotype (presence of at least one C at rs713598) 2

3 Phenotype Genotype 33% 35.1% 26.3% 67% 38.6% Yes No GG GC CC Did the strip taste bitter to you? Yes = 67% (n = 117) TAS2R38 GG or GC = 64.9% (n = 57) What are some reasons the genotype and phenotype might not match? 3

4 Genetic basis of taster phenotype It s been used as a simple example of Mendelian inheritance (eg. tasting as autosomal dominant). Variation in the TAS2R38 gene accounts for 55 85% of the variation in PTC sensitivity. John McDonald, The Myth of PTC testing Pharmacogenomics: Clinical Decision Making James Stevenson, PharmD, MS Assistant Professor of Pharmacy & Therapeutics 4

5 CYP2D6: best understood MR = Meyer UA. Nat Rev Genet. 2004;5(9): PGx decision making Important factors to consider: 1. functional consequence 2. variant frequency in population eg. rs GA? 5

6 Group 1: Answer the following about the SNP rs : In what gene is it located and what is the function? What haplotype (star nomenclature) is associated with this SNP? Are there any reported functional consequences associated with this SNP/haplotype? Group 2: Answer the following about CYP2D6: What types of genetic variation are known to occur in this gene? What drugs do genetic variations in CYP2D6 impact? What is phenocopying and what are its clinical implications? Group 3: Answer the following about allopurinol: What haplotype is associated with allopurinol response? Do any clinical guidelines recommend using genetic test results in practice? Is the risk haplotype more common in some racial groups than others? Group 4: Answer the following about citalopram: What gene(s) have clinical guidelines that can be applied to citalopram? What other genes have been studied for association with citalopram response? Group 1 6

7 Group 1 What haplotype (star nomenclature) is associated with this SNP? Group 2 What types of genetic variation are known to occur in this gene? alleles that led to a complete loss of CYP2D6 activity reduced function and even hyperfunctional CYP2D6 alleles The CYP2D6 copy number has been found to be from Each functional copy of CYP2D6 that is present increases the rate of metabolism of CYP2D6 substrates significantly 7

8 Group 2 What drugs do genetic variations in CYP2D6 impact? What is phenocopying and what are its clinical implications? Group 3 What haplotype is associated with allopurinol response? Do any clinical guidelines recommend using genetic test results in practice? Is the risk haplotype more common in some race groups than others? 8

9 Group 4 What gene(s) have clinical guidelines that can be applied to citalopram? What other genes have been studied for association with citalopram response? PGx decision making Important factors to consider: 1. functional consequence 2. variant frequency in population 3. drug dependence on pathway Metabolite A Enzyme 1 Enzyme 2 Drug 80% 5% Metabolite B Enzyme 3 5% Metabolite A conjugate Excreted 9

10 Active moiety and therapeutic index Parent Drug Enzyme Metabolite PM/IM EM UM If parent drug is active moiety If metabolite is active moiety Parent Metabolite Toxicity Metabolite Parent Efficacy Metabolite Parent Failure Failure Efficacy Toxicity Empey PE. Crit Care Med (6 Suppl):S PGx decision making Important factors to consider: 1. functional consequence 2. variant frequency in population 3. drug dependence on pathway 4. active moiety and therapeutic index 5. concomitant drug therapy (DIs) and clinical factors 6. Is there clinical outcome data? What do established guidelines recommend? 10

11 CPIC Guidelines Level definitions for CPIC Gene/Drug Pairs CPIC, 10/2014 PGx decision making Important factors to consider: 1. functional consequence 2. variant frequency in population 3. drug dependence on pathway 4. active moiety and therapeutic index 5. concomitant drug therapy (DIs) and clinical factors 6. Is there clinical outcome data? What do established guidelines recommend? 7. Are tests available? Relative to PK/PD, the impact of PGx on PK (eg. drug metabolizing enzymes) is best understood. WHY? 11

12 Genetics loads the gun and environment pulls the trigger. Dr. Francis Collins Genetics Environ ment Trigger Outcome For chronic health conditions especially Genetics is predictive, not deterministic! Pathway Genetics Newsroom, 8/10/2010, accessed 10/2014 Pharmacogenomics: Predicting phenotype from variant level data Solomon Adams, PharmD Clinical Pharmacogenomics Fellow Graduate Student, Pharmaceutical Sciences 12

13 Identify your patient s CYP2C19 genotype and predicted phenotype Haplotype rs rs rs rs rs rs rs rs rs rs *1 G G A C G T T G C C *2 A *3 A *4A G *4B G T *5 T *6 A *7 A *8 C *9 A *10 T *17 T 13

14 CYP2C19 COMMON ALLELES Allele dbsnp Nucleotide* Protein** Effect %MAF (EU/AA/ALL) *1 None No variant None Normal 62.2/57.9/68.4 *2 rs c.681g>a Splicing Defect Loss of function 14.8/16.5/15.4 *3 rs c.636g>a p.trp212* Loss of function 0.02/0.05/0.03 *4 rs c.1a>g p.met1leu Loss of function 0.33/0.02/0.22 *5 rs c.1297c>t p.arg433trp Loss of function 0.0 *6 rs c.395g>a p.arg132gln Loss of function 0.05/0.02/0.04 *7 rs c.819+2t>a Splicing Defect Loss of function 0.0 *8 rs c.358t>c p.trp120arg Loss of function 0.20/0.14/0.18 *9 rs c.431g>a p.arg144his Unknown 0.0/1.16/0.39 *10 rs c.680c>t p.pro227leu Unknown 0.0/0.23/0.08 *17 rs c.-806c>t Promoter Increased transcription 22.4/23.5/15.3 Allele *1 *2 *3 *4 *5 *6 *7 *8 *9 *10 *17 *1 EM IM IM IM IM IM IM IM IM IM UM *2 PM PM PM PM PM PM PM PM PM IM *3 PM PM PM PM PM PM PM PM IM *4 PM PM PM PM PM PM PM IM *5 PM PM PM PM PM PM IM *6 PM PM PM PM PM IM *7 PM PM PM PM IM *8 PM PM PM IM *9 PM PM IM *10 PM IM *17 UM EM: extensive (normal) metabolizer; IM: intermediate metabolizer; PM: poor metabolizer; UM: ultrarapid metabolizer Adapted from CPIC, 10/

15 Patient presents to Cath Lab P2Y12 inhibitor initiated CYP2C19 genotype testing (if not previously done) UM EM IM PM clopidogrel 75 mg daily ticagrelor 90 mg BID or prasugrel 10 mg daily How many had a dataset that was a: A. EM (extensive normal metabolizer)? B. IM (intermediate metabolizer)? C. PM (poor metabolizer)? D. UM (ultra-rapid metabolizer)? 15

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17 Apply the CYP2C19 genotype and predicted phenotype and the PGx clinical decision making process to determine the relevance for other drugs: carbamazepine, omeprazole, phenytoin Important factors to consider: 1. functional consequence 2. variant frequency in population 3. drug dependence on pathway 4. active moiety and therapeutic index 5. concomitant drug therapy (DIs) and clinical factors 6. Is there clinical outcome data? What do established guidelines recommend? 7. Are tests available? 17

18 Application of the PGx clinical decision making process Gene: CYP2C19 Carbamazepine Omeprazole Phenytoin Functional Consequences to Variation Variant Frequency Drug Dependent on Pathway Active moiety and Therapeutic Index Drug-Drug Interactions and Clinical Factors Outcome Data and/or Guidelines Exist Importa Active nt CPIC: No Partial Active Minor DPWG: Yes Partial, Minor Active Importa nt Available Tests Pharmacogenomics: Leading clinical applications Philip Empey, PharmD, PhD, BCPS Assistant Professor, Pharmacy & Therapeutics Associate Director for Pharmacogenomics, Institute of Personalized Medicine 18

19 TPMT & Thiopurines TPMT = Thiopurine methyl transferase TPMT & Thiopurines: is this really important? Heart transplant patient (later found thiopurine methyltransferase deficient) taking azathioprine 19

20 TPMT & Thiopurines FDA labeling of azathioprine recommends geno- or phenotyping: First CPIC guideline, 3/2011 (updated 2/2013) Relling et al. Clin Pharmacol Ther. 2011:89 3, Relling et al. Clin Pharmacol Ther. 2013: 93(4): Simvastatin & SLCO1B1 Myopathy is a rare, but serious, ADR. Monitoring is routinely performed. SLCO1B1 is the simvastatin hepatic uptake transporter 625 T>C (*5) has decreased activity Caucasian = 12 20% Asian = 6 19% A. American =1 4% Japanese =0.7% Kim et al. CP&T. 2005;78:

21 Simvastatin & SLCO1B1 SLCO1B1 variant = risk of simvastatin-induced myopathy Kim et al. CP&T. 2005;78: Link E et al. NEJM. 2008;359(8): Simvastatin & SLCO1B1 60% of myopathy cases attributed to *5 Risk 4.5 fold (1 copy); 16.9 fold (2 copies) Link et al. NEJM. 2008;359(8):

22 Simvastatin & SLCO1B1 Nothing in the FDA product label Statins & SLCO1B1 Why does the increased risk not extend to all drugs in class? Voora et al. J Am Coll Cardiol 2009;54(17):

23 Warfarin & CYP2C9/VKORC1 Commonly used anticoagulant with narrow therapeutic index, in top 10 drugs for ADRs Coagulation Polygenic PG issues: Genetic variants in both its metabolism and drug target M O R E Cavallari LH et al. Curr Opin Mol Ther 2009;11(3): CYP2C9/VKORC1 & Warfarin: dose requirements Daily Warfarin Dose (mg) 6 *1/*1 *1/*2 + *1/*3 *1/*3 *2/*2 *2/*3 + *3/* GG GA AA GG GA AA GG GA AA GG GA AA VKORC1 rs Genotype GG GA AA Adapted from: Sconce, et al. Blood. 2005;106(7) 23

24 CYP2C9/VKORC1 & Warfarin Together, account for 30 40% of variability in doses Gage/International Warfarin Consortium algorithms better than fixed dose or clinical variables only especially for those requiring <21 mg/wk or >49 mg/wk FDA updated labeling in 2007 and 2010, but did not mandate testing Gage et al. CP&T. 2008;84(3): Klein et al. NEJM. 2009;360(8): CYP2C9/VKORC1 & Warfarin Warfarindosing.org Verschuren et al. Eur Heart J (2012) 33 (2):

25 Warfarin case Ian M. Ableider is a 68 year old 5 8, 84 kg nonsmoking Caucasian male who was stable on warfarin 4 mg daily 2 years ago for Afib and was cardioverted. Today he is being restarted on warfarin for new onset of Afib to achieve a target INR of 2.5. PGx: VKORC AG & CYP2C9 *3/*3 Labs: INR 1.1; normal renal/liver function Meds: Simvastatin 20 mg daily Amiodarone 200 mg daily Lisinopril 10 mg daily Metformin 500 mg BID Paroxetine 20 mg daily 25

26 CYP2C9/VKORC1 & Warfarin: Latest data COAG (n=1015) 4 weeks 45.2% vs 45.4% p = 0.91 EU-PACT (n=455) TTR through 12 wks 67.4 vs 60.3% p < EU-PACT (n=548) TTR through 12 wks 61.6 vs 60.2% p = 0.52 GIFT is ongoing Kimmel et al. NEJM. 2013; 369: Pirmohamed et al. NEJM. 2013; 369: Talitha et al. NEJM. 2013; 369: Identify your patient s genotypes and predicted phenotypes using the interpretation engine Patient case application 26

27 Patient case HF is a 54 y/o asian male that presented to your hospital 2 days ago with c/o of severe substernal chest pressure, diaphoresis, and feeling of impending doom. He was diagnosed with STEMI and taken to the cath lab for primary PCI. He was found to have a 100% occlusion of his left anterior descending artery and a drug eluting stent (DES) was placed. His/Her clinical course was complicated by new onset atrial fibrillation. Discharge medications include: ASA 81 mg daily clopidogrel 75 mg dao;u Metoprolol 50 mg bid Carbamazepine 200 mg daily Lisinopril 10 mg daily simvastatin 20 mg daily Omeprazole 20 mg daily Warfarin 7.5 mg daily (has received one dose of 10 mg so far) Pre emptive PGx test results on file: CYP2C19 CYP2C9 SLCO1B1 VKORC1 DINNER BREAK 27

28 Pharmacogenomics: Applications to Community Rx Lucas Berenbrok, PharmD Assistant Professor of Pharmacy & Therapeutics Prescribing Transmission Dispensing Administration Monitoring 28

29 Case Report 65 yo male Presenting with Rx for clopidogrel post MI/PCI CYP2C19 genotyping offered to patient by community pharmacist Results: *1/*2 Prasugrel 10 mg once daily recommended by pharmacist to replace clopidogrel Drug therapy accepted by prescribing physician J Pharm Pract Feb 13;27(4): Test American Pharmacists Association 29

30 ACCESS PAYMENT CARE Nationwide Chains Regional Chains Independent Community Pharmacy 30

31 PATIENT PHARMACIST PHYSICIAN 31

32 Data Evidenced-based medication use Better health outcomes Current models partner with community pharmacists to optimize medication use. Patients are engaged via direct-to-consumer tests available at community pharmacies. Pharmacists may contribute to the PGx Tipping Point as connectors and mavens to pharmacogenomic data informing safe and effective medication use. 32