Clinical Implementation of Pharmacogenetics Mary V. Relling, Pharm.D.

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1 Clinical Implementation of Pharmacogenetics Mary V. Relling, Pharm.D.

2 Actionable pharmacogenetic gene/drug pairs have been known for a long time Primaquine G6PD Codeine CYP2D6 Thiopurines TPMT 5FU DPYD Abacavir HLA-B

3 Cumulative Incidence of 6mp Dose Alterations to Prevent Toxicity During Continuation Therapy of Total XII Myelosuppression was related to TPMT genotype on Total XII (BEFORE we started adjusting doses based on TPMT testing) CI Years About 35% for TPMT hets. Homozygous Wild Types Heterozygotes Mutants Relling et al JNCI, 1999

4 0.3 Myelosuppression Cumulative Incidence of grade 3 was and 4 severe not life related threatening febrile to neutropenia TPMT and genotype TPMT on Total XIII (AFTER we started adjusting doses based on TPMT testing) 0.25 Cumulative incidence Reduced to ~ 10% for hets Time of maintenace therapy TPMT Wild type TPMT Variant Stocco et al Clin Pharm Ther 2009

5 Relapse was not related to TPMT genotype on Total XIII (AFTER we started adjusting doses based on TPMT testing) despite preemptive 6MP dose decreases in pts with TPMT defect CI of relapse P = 0.43 N= Time in Years N=15 wild type heterozygote Relling et al, Blood, 2006

6 Multivariate Analysis showed lower risk of Abacavir Hypersensitivity when HLA-B screening was used. Mallal S et al. N Engl J Med 2008;358:

7 Lower risk of High INRs with genotypeguided dosing of warfarin GIFT Trial, Gage et al, JAMA, 2017

8 Actionable pharmacogenetic gene/drug pairs have been known for a long time. use in the clinic still rare Primaquine G6PD Codeine CYP2D6 Thiopurines TPMT 5FU DPYD Abacavir HLA-B

9 The use of pharmacogenetics-guided prescribing is not widespread 2013 national survey of pharmacies in a hospital setting in the US found: 82% hospitals did not offer testing 7% of hospitals offered pharmacogenetic testing Up from 2.7% in 2009 Genomically-informed prescribing remains underutilized Pedersen CA, et al. Am J Health Syst Pharm. 2014;71:

large academic center but no directed efforts at preemptive genotyping 132,340 patients and 3,211,797 hospital/clinic visits, 268,262 medication orders for 95 drugs with germline PGEN testing

10 large academic center but no directed efforts at preemptive genotyping 132,340 patients and 3,211,797 hospital/clinic visits, 268,262 medication orders for 95 drugs with germline PGEN testing mentioned in their FDA-approved drug labels (49 of which were actionable by CPIC) <1% of prescriptions for those 95 drugs were accompanied by testing 1.5% even when the label recommended or required (rather than just mentioned) testing

11 + 9 other programs listed

13 2009/2010 Survey of pgen experts (PGRN and ASCPT): top 3 challenges to implementing pharmacogenetics in the clinic 95% of respondents selected: process required to translate genetic information into clinical actions Next 2 responses Genotype test interpretation (e.g. using genotype information to assign phenotype) Providing recommendations for selecting the drug/gene pairs to implement Clin Pharmacol Ther :464-7.

14 At St. Jude, we are approaching implementation on 2 fronts St. Jude Children s Research Hospital PG4KDS Protocol

15 CPIC website:

16 Academic, Hospital, Health Care Systems Industry 2017 > 200 Members

Assumption of CPIC Guidelines CPIC guidelines are designed to help clinicians understand HOW available genetic test results should be used to optimize drug therapy Not WHETHER tests should be ordered

17 Assumption of CPIC Guidelines CPIC guidelines are designed to help clinicians understand HOW available genetic test results should be used to optimize drug therapy Not WHETHER tests should be ordered Key Assumption: Clinical high-throughput and preemptive genotyping will become more widespread Clinicians will be faced with having patients genotypes available even if they did not order test with drug in mind

18 Posted on cpicpgx.org and capitalize on PharmGKB resources Freely available, no limits on use Peer reviewed, CPT first right of refusal to publish, standardized format, minimum set of elements Grading of evidence and of recommendations Can be updated on CPIC website ahead of publications Authorship, COI policy Closely follow IOM practices Curr Drug Metab Feb;15(2):209-17

19 Clin Pharmacol Ther Feb;93(2):153-8 Clin Pharmacol Ther Apr;93(4): Clin Pharmacol Ther May;93(5): Clin Pharmacol Ther Sep;94(3): Clin Pharmacol Ther Sep;94(3): Clin Pharmacol Ther Aug 29. Epub Clin Pharmacol Ther Feb;95(2):141-6.

20 CPIC guideline genes (Sept 2017)

21 CPIC website:

23 CPIC website:

24 Assignment of CPIC levels to gene/drug pairs e.g. TPMT/mercaptopurine CYP4F2/warfarin e.g. CYP2D6/propranolol e.g. GSTM1/cisplatin

25 Grading system for strength of prescribing recommendations in CPIC guidelines Strength Strong Moderate Optional No Recommendation Definition The evidence is high quality and the desirable effects clearly outweigh the undesirable effects. There is a close or uncertain balance as to whether the evidence is high quality and the desirable clearly outweigh the undesirable effects. The desirable effects are closely balanced with undesirable effects, or the evidence is weak or based on extrapolations. There is room for differences in opinion as to the need for the recommended course of action. There is insufficient evidence, confidence, or agreement to provide a recommendation to guide clinical practice at this time.

26 Strength of Prescribing Recommendation differs by phenotype/drug within many guidelines

27 30,000 page views gene/drug pairs 46 A level 99 B level 83 C level 124 D level

28 Sept 2017

29 How many gene/drug pairs should be used in the clinic? ~ 1200 chemical entities approved as drugs ~ 18,000 genes Actionable: ~ 31 genes, ~ 87 drugs (~ 30 guidelines) picgenedrugpairs Relling & Evans, Nature, 2015

31 CPIC guidelines Gantt chart: is this scalable? Gene - Drug Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 TPMT NUDT15-- thiopurines CYP2C19 - clopidogrel Tr. T CYP2C9, VKORC1 - CYP4F2 warfarin Tr. T CYP2D6 - codeine Tr. T HLA-B - abacavir SLCO1B1 - simvastatin HLA-B - allopurinol CYP2D6, CYP2C19 - TCAs Tr. T HLA-B - carbamazepine Tr. T DPYD - 5FU / capecitabine Tr. T IL28B - pegintron CFTR-Ivacaftor Tr. T G6PD - rasburicase Tr.T CYP2C9/HLA-B - phenytoin CYP2D6 - SSRIs CYP3A5-tacrolimus UGT1A1 - atazanavir CYP2C19-voriconazole Tr.T CYP2D6-tamoxifen Tr.T CYP2D6-ondansetron Tr.T RYR1-succinylcholine Tr.T CYP2B6 - efavirenz Tr.T CYP2C19/CYP2D6-antidepressants (SNRI/NaSSA) Tr.T CYP2C19-PPIs Tr.T CYP2D6-ADHD drugs Tr.T G6PD-other drugs Tr.T CYP2C9-celecoxib Tr. T CYP2D6-antipsychotics Tr.T CYP2B6-NNRTI CYP2D6-B-blockers Factor V Leiden-estrogen OC MTHFR-methotrexate/others NAT2-isoniazid CYP2C19-diazepam CYP2D6-misc. drugs

32 Ranking of gene/drug pairs without CPIC guidelines

33 CPIC to do list CYP2D6 - tamoxifen RYR1, CACNA1S - inhaled anesthetics CYP2B6 efavirenz CYP2D6 - ADHD drugs (e.g,. atomoxetine, methylphenidate) CYP2C19 - PPIs (e.g., esomeprazole, omeprazole, etc.) CYP2C9 - NSAIDS (e.g., celecoxib, flurbiprofen, diclofenac) CYP2D6 - antipsychotics (e.g., aripiprazole, risperidone, others) CYP2C19, CYP2D6 - antidepressants (e.g.,snri/nassa) ABCB1 with update)

34 Guideline updates

35 Maintaining links with everyone in this space is challenging

37 We are approaching implementation on 2 fronts at St. Jude St. Jude Children s Research Hospital PG4KDS Protocol Long-term goal: preemptive pharmacogenetic testing as the standard of care for everyone All CPIC guidelines.

38 Goal: PG4KDS protocol Migrate pharmacogenetic tests from the laboratory (array-based) into routine patient care, to be available preemptively Exclusion criteria: Patients who have received a prior allogeneic stem cell transplant Patient who have received a prior liver transplant

39 PG4KDS: The Process Patient consent Blood sample Genotyping (230 genes) Research database Patient education Clinical decision support Select results put in EHR Hoffman JM, et al. Am J Med Genet C Semin Med Genet. 2014;166C:45.

40 Implemented Gene/Drug Pairs TPMT CYP2D6 SLCO1B1 CYP2C19 DPYD UGT1A1 CYP3A5 NUDT15 CYP2C9

41 TPMT and thiopurines CYP2D6 and codeine CYP2D6 and tramadol Implementation Timeline: 9 Genes and 22 Drugs Implemented CYP2D6 and paroxetine, fluoxetine, amitriptyline CYP2D6 and ondansetron SLCO1B1 and simvastatin CYP2D6 and oxycodone CYP2C19 and clopidogrel DPYD and fluoropyrimidines CYP2C19/CYP2D6 and amitriptyline UGT1A1 and atazanavir CYP2C19 and voriconazole CYP3A5 and tacrolimus CYP2C19/CYP2D6 and TCAs NUDT15 and thiopurines CYP2C9 and celecoxib

42 9 Genes and 22 Drugs Implemented CYP2D6 (17%) Codeine Oxycodone Tramadol Amitriptyline, Clomipramine, Imipramine, Trimipramine Doxepin Fluoxetine Paroxetine Ondansetron CYP2C19 (62%) Clopidogrel Amitriptyline, Clomipramine, Imipramine, Trimipramine Doxepin Voriconazole CYP3A5 (41%) Tacrolimus SLCO1B1 (13%) Simvastatin TPMT/NUDT15 (11%) Mercaptopurine Thioguanine Azathioprine DPYD (0.4%) Fluorouracil Capecitabine UGT1A1 (28%) Atazanavir CYP2C9 (32%) Celecoxib Percentages in parenthesis indicate the proportion of patients enrolled on the PG4KDS protocol who have a high-risk genotype for that gene.

43 90% of patient have at least one highrisk genotype in their EHR n=3819 4% 10% 18% 10 high-risk genotypes 21 high-risk genotype 32 high-risk genotypes 32% 43 high-risk genotypes 54 high-risk genotypes 36% 90% 65 high-risk genotypes 7 Unpublished data generated 08/01/2017

44 PG4KDS by numbers Number of patients % Approached for consent Enrolled on protocol Re-consented at age of majority Incidental findings % Unpublished data (Sep 2017)

How do we get from genotype to interruptive CDS for prescribing? g.94761900c>t + g.94762706a>g Functions to alleles (e.g. CYP2C19*4B = no function) Alleles to diplotypes (e.g. g.94761900ct + g.

45 How do we get from genotype to interruptive CDS for prescribing? g c>t + g a>g Functions to alleles (e.g. CYP2C19*4B = no function) Alleles to diplotypes (e.g. g ct + g ag = CYP2C19*1/*4B) Diplotypes to phenotypes (e.g. CYP2C19*1/*4B = intermediate metabolizer) Interpretation of phenotypes (e.g. CYP2C19 intermediate metabolizer = altered dosing recommendations for TCAs but not clopidogrel) Phenotypes to actionability (e.g. intermediate metabolizer + Rx for amitriptyline = interruptive alert)

47 CPIC tables allow translation of genetic test results to actionability Genotypes to alleles (e.g. g c>t + g a>g = CYP2C19*4B) Functions to alleles (e.g. CYP2C19*4B = no function) Alleles to diplotypes (e.g. g ct + g ag = CYP2C19*1/*4B) Diplotypes to phenotypes (e.g. CYP2C19*1/*4B = intermediate metabolizer) Interpretation of phenotypes (e.g. CYP2C19 intermediate metabolizer = altered dosing recommendations for TCAs but not clopidogrel) Phenotypes to actionability (e.g. intermediate metabolizer + Rx for amitriptyline = interruptive alert)

48 CPIC Allele definition table: genotypes to alleles, and alleles to function

49 CPIC tables allow translation of genetic test results to actionability Genotypes to alleles (e.g. g c>t + g a>g = CYP2C19*4B) Functions to alleles (e.g. CYP2C19*4B = no function) Alleles to diplotypes (e.g. g ct + g ag = CYP2C19*1/*4B) Diplotypes to phenotypes (e.g. CYP2C19*1/*4B = intermediate metabolizer) Interpretation of phenotypes (e.g. CYP2C19 intermediate metabolizer = altered dosing recommendations for TCAs but not clopidogrel) Phenotypes to actionability (e.g. intermediate metabolizer + Rx for amitriptyline = interruptive alert)

50 Variants must be phased to assign diplotypes for pharmacogenes CPIC Gene Var/var different than var/wt? TPMT Yes CYP2C19 Yes CYP2D6 Yes DPYD Yes CYP2C9 Yes SLCO1B1 Yes HLA-B No VKORC1 Yes IL28-B Yes CFTR No G6PD Yes UGT1A1 Yes CYP3A5 Yes

51 From genotype or sequencing data, call genecentric haplotypes and diplotypes not just variants

52 PharmCAT To automate the annotation of.vcf files with the appropriate haplotypes or diplotypes from the CPIC guideline genes, and generate a report with the corresponding CPIC guideline prescribing recommendations

53 CPIC tables allow translation of genetic test results to actionability Genotypes to alleles (e.g. g c>t + g a>g = CYP2C19*4B) Functions to alleles (e.g. CYP2C19*4B = no function) Alleles to diplotypes (e.g. g ct + g ag = CYP2C19*1/*4B) Diplotypes to phenotypes (e.g. CYP2C19*1/*4B = intermediate metabolizer) Interpretation of phenotypes (e.g. CYP2C19 intermediate metabolizer = altered dosing recommendations for TCAs but not clopidogrel) Phenotypes to actionability (e.g. intermediate metabolizer + Rx for amitriptyline = interruptive alert)

54 CYP2C19 diplotype/ phenotype table

55 Diplotypes entered on Pharmacogenetics Tab: not encounter-specific Consult is one place for passive CDS

56 Passive CDS: interpretation of pgen test results always available

57 Some consults now based on results of > 1 gene: e.g. NUDT15/TPMT for thiopurines

58 Templates based on deconstructing the consult into sections: scalable Phenotype Assignment Diplotype Interpretation Phenotype interpretation, medications Prescribing Recommendations Educational Link Consult Builder Hicks et al (CPT 2012)

63 Same database used to create consults and alerts is used to populate the St. Jude formulary: another source of passive CDS

64 Pharmacogenetics Resources in St. Jude Formulary

68 CPIC tables allow translation of genetic test results to actionability Genotypes to alleles (e.g. g c>t + g a>g = CYP2C19*4B) Functions to alleles (e.g. CYP2C19*4B = no function) Alleles to diplotypes (e.g. g ct + g ag = CYP2C19*1/*4B) Diplotypes to phenotypes (e.g. CYP2C19*1/*4B = intermediate metabolizer) Interpretation of phenotypes (e.g. CYP2C19 intermediate metabolizer = altered dosing recommendations for TCAs but not clopidogrel) Phenotypes to actionability (e.g. intermediate metabolizer + Rx for amitriptyline = interruptive alert)

71 CDS needed for Clinical actionability on genetic test results Interruptive alerts (active CDS): Pre-test situation: Check for genetic test and, if missing, guide prescriber to consider ordering the test Post-test situation: Test result is high-risk and advice for prescribing alternatives should be presented Test result is low-risk and no interruptive alert should be fired

72 Pre-test alerts contains prescribing and testing recommendations if a patient has not been genotyped: driven off the ABSENCE of a test result

73 Post-test alerts contain prescribing recommendations based on the PRESENCE of a high risk test result

74 High-risk pharmacogenetic phenotypes are added to the problem list Problem list entries serve as the discrete data element for interruptive point of care CDS

75 Drive CDS off of problem list entry

76 Post-test alert can incorporate non-genetic info too: based on CYP2C19 phenotype, route of administration, age

77 Post-test alert: based on 2 genes affecting same drug

Not all drugs supported by CDS yet 11 year old boy at week 102 of ALL continuation therapy intermittent thrombocytopenia, episode of hematemesis, started omeprazole another episode of hematemesis;

78 Not all drugs supported by CDS yet 11 year old boy at week 102 of ALL continuation therapy intermittent thrombocytopenia, episode of hematemesis, started omeprazole another episode of hematemesis; endoscopy showed esophageal varices AFTER consultation for increase in liver enzymes, found to have CYP2C19*17/*17 diplotype already in EHR, but no CDS built for PPIs Swen JJ et al 662 VOLUME 89 NUMBER 5 MAY

79 CDS needed for Clinical actionability of Interruptive alerts (active CDS): Pre-test situation: genetic test results Check for genetic test and, if missing, guide prescriber to consider ordering the test Post-test situation: Test result is high-risk and advice for prescribing alternatives should be presented Test result is low-risk and no interruptive alert should be fired Interpretations (passive CDS) But genetic test names, results, phenotypes (problems, diagnoses) are not standardized, making it difficult for EHR vendors to support efforts to build CDS based on genetic tests

81 Standardized Terms-Allele function Term/Gene Category Allele Functional Status-all genes Final Term* Functional Definition Example diplotypes/alleles Increased Function Function greater than normal function CYP2C19*17 Normal Function Fully functional/wild-type CYP2C19*1 Decreased Function Function less than normal function CYP2C19*9 No Function Non-functional CYP2C19*2 Unknown Function No literature describing function or CYP2C19*29 the allele is novel Uncertain Function Literature supporting function is CYP2C19*12 conflicting or weak

82 Term/Gene Category Phenotype-Drug Metabolizing Enzymes (CYP2C19, CYP2D6, CYP3A5, CYP2C9, TPMT, DPYD, UGT1A1) Phenotype- Transporters (SLCO1B1) Phenotype-High risk genotype status (HLA-B) Standardized Terms-Phenotype Final Term* Functional Definition Example diplotypes/alleles Ultra-rapid Metabolizer Rapid Metabolizer Increased enzyme activity compared to rapid metabolizers. Increased enzyme activity compared to normal metabolizers but less than ultra-rapid metabolizers. Two increased function alleles, or more than 2 normal function alleles Combinations of normal function and increased function alleles Normal Metabolizer Fully functional enzyme activity Combinations of normal function and decreased function alleles Intermediate Metabolizer Decreased enzyme activity (activity between normal and poor metabolizer) Combinations of normal function, decreased function, and/or no function alleles Poor Metabolizer Little to no enzyme activity Combination of no function alleles and/or decreased function alleles Increased Function Increased transporter function One or more increased function compared to normal function. alleles Normal Function Fully functional transporter function Combinations of normal function and/or decreased function alleles Decreased Function Decreased transporter function (function between normal and poor function) Combinations of normal function, decreased function, and/or no function alleles Poor Function Little to no transporter function Combination of no function alleles and/or decreased function alleles Positive Detection of high-risk allele Homozygous or heterozygous for high-risk allele Negative High risk-allele not detected No copies of high-risk allele Term/Gene Category CYP2C19*17/*17 CYP2D6*1/*1XN CYP2C19*1/*17 CYP2C19*1/*1 CYP2C19*1/*2 CYP2C19*2/*2 SLCO1B1*1/*14 SLCO1B1*1/*1 SLCO1B1*1/*5 SLCO1B1*5/*5 HLA-B*15:02

83 Can t detect duplicate testing unless standardized test names are adopted

84 Patient education

85 PG4KDS by numbers Number of patients % Approached for consent Enrolled on protocol Re-consented at age of majority Request to receive result letter % Incidental findings % Unpublished data (Sep 2017)

86 Patient Letters include: Phenotype (metabolizer status) Pie chart of phenotype frequencies Drug considerations

87 Patients who opt-in to receive results: letters are mailed, posted to EHR, available via pt portal Copy of letter is poster in the medical record

88 Swen J et al, Pharmacogenomics J, 2017

89 Medication Information Sheets

90 Do You Know Patient Information Sheets

91 Pharmacogenetic testing as metrics for Patient safety/quality TPMT-guided thiopurine dosing CYP2D6 testing before codeine

92 100% 90% 80% Percentage of thiopurine naïve patients diagnosed with ALL who had a known TPMT genotype prior to initiating thiopurine therapy at St. Jude* 93% [VALUE] 92% 93% 95% 70% 60% 50% 40% TRUE FALSE Patients with a known TPMT genotype Patients with no known TPMT genotype 30% 20% 10% 0% * Patients with an unknown TPMT genotype who initiated thiopurine therapy after an allogeneic HSCT were excluded from this reporting

93 Inverse relationship between utilization of CYP2D6 genotyping and the number of patients who had a pretest alert fire Gammal RS, et al. Pediatrics. 2016;138(1):e

94 No codeine was prescribed to patients with a CYP2D6 ultra-rapid or poor metabolizer phenotype (n=621) Gammal RS, et al. Pediatrics. 2016;138(1):e

95 Drug Thiopurines Codeine Tramadol Amitriptyline Fluoxetine Paroxetine Oxycodone Simvastatin Ondansetron Clopidogrel Fluorouracil Capecitabine Gene TPMT CYP2D6 CYP2D6 CYP2D6 CYP2D6 CYP2D6 SLCO1B1 CYP2D6 CYP2C19 DPYD Adverse Outcomes Myelosuppression Increased toxicity or therapy failure Increased toxicity or therapy failure Increased toxicity or therapy failure Increased toxicity or therapy failure Increased toxicity or therapy failure Myopathy Poor N/V control Increased or reduced platelet inhibition Implementation Status Live Live Live Live Live Live Live Live Live Live Clinical impact of negative outcomes significant Scientific evidence for drug gene effect Patient target identifiable before they receive drug Alternative therapy available Gene added to DMET tracker Gene specific look up tables created Consult template written Consult database updated CDS language developed Patient letters Gene specific "Do You Know " sheet Patient medication card N/A N/A PGEN formulary table updated Drug monograph updated in formulary N/A N/A St. Jude PG4KDS webpage updated Staff education Competencies POC Approval P&T Communication Increased toxicity Go-Live Date 5/2011 5/2011 2/2012 5/2012 5/2012 5/2013 5/2013 2/2013 6/2013 5/2014

96 PG4KDS Website

100 CPIC Acknowledgements Stanford Teri Klein Russ B. Altman Michelle Whirl-Carrillo Li Gong Katrin Sangkuhl St. Jude Kelly Caudle Cyrine E. Haidar James M. Hoffman Rose Gammal Stuart Scott, Mt. Sinai Sandy Aronson, Partners/Harvard Bob Freimuth, Mayo CPIC members and observers CPIC guideline authors DIGITizE

PG4KDS Protocol Clinical Implementation of Pharmacogenetics Cyrine Haidar Kristine Crews James Hoffman Shane Cross Jennifer Hockings Don Baker & Clinical Informatics Charles Mullighan Aditya Gaur

101 PG4KDS Protocol Clinical Implementation of Pharmacogenetics Cyrine Haidar Kristine Crews James Hoffman Shane Cross Jennifer Hockings Don Baker & Clinical Informatics Charles Mullighan Aditya Gaur Ulrike Reiss Alicia Huettel Cheng Cheng Amar Gajjar RNs: Sheri Ring, Lisa Walters, Paula Condy, Terri Kuehner, Margaret Edwards, Shannon Gibbs, Melinda Wood Austin Springer Nancy Kornegay Wenjian Yang Colton Smith Alejandro Molinelli Alberto Pappo Melissa Hudson Ching-Hon Pui Sima Jeha Kim Nichols William E. Evans PG residents: Kevin Hicks, Gillian Bell, Mark Dunnenberger Rose Gammal, Amy Pasternak, Jennifer Hockings Ulrich Broeckel, M.D. Rachel Lorier Amy Turner

102

103 Clin Pharmacol Ther Jul;92(1):112-7.

104 Informatics section added to supplement for HLA-B Genotype and Abacavir Dosing: 2014 Update Tables with drug and gene codes Figures that describe workflow Incorporation of genetic test CDS when abacavir ordered Translation table Sample CDS text Clin Pharmacol Ther Feb 21

105 HLA-B*57:01 Pharmacogenetic Test Result: Clinical Implementation Workflow for EHR

106 HLA-B*57:01 Pharmacogenetic Test Result: Clinical Implementation Workflow for EHR

107 SLCO1B1 Genotype and Simvastatin: Point of Care Clinical Decision Support Simvastatin order initiated SLCO1B1 genetic test results on file? Yes Priority result? c No No post-test alert required; continue with drug order No CDS Pre-test Alert Message a (additional action may be considered) b Yes 1 2 CDS Post-test alert d or notify prescriber with recommendation Note: Circled numerals refer to Supplementary Table 12 Supplemental Figure S3. SLCO1B1 Genotype and Simvastatin: Point of Care Clinical Decision Support a See Supplementary Table S12 for diplotype/phenotype specific pre-test alert example. b Additional actions may include ordering a pharmacogenetic test, preventing the clinician from ordering the medication or allowing the clinician to cancel out of the alert. c Priority result defined as a genetic test result that results in a change in drug, drug dose, or drug monitoring. d See Supplementary Table S12 for diplotype/phenotype specific post-test alert example.

108

109 Translation Tables Table for abacavir is simple: Test Result for HLA-B*57:01 b Examples of Diplotypes c Interpreted Phenotype d Negative X/X Low Risk of abacavir hypersensitivity Positive X/57:01 or 57:01/57:01 High Risk of abacavir hypersensitivity SLCO1B1/Simvastatin Many more diplotypes All possible diplotype combinations Post to PharmGKB Diplotypes of known functional significance CPIC Supplement Table

110

111 PG4KDS: Changing Testing Platform Transitioning testing platforms: From: DMET Plus Array To: PharmacoScan Almost ready to switch over

112 Gene Differences between DMET Plus and PharmacoScan Variants Tested by DMET Plus Variants Tested by PharmacoScan Comments CYP2C *7 (probably normal function) CYP2D CYP2D6 copy number on PharmacoScan CYP3A S100C (unknown function) DPYD N635K (unknown function) G6PD SLCO1B UGT1A *36 (increased function) F83I (unknown function)

113 New genes tested on PharmacoScan Gene HLA-B*15:02 HLA-B*58:01 HLA-A*31:01 Variants Tested by DMET Plus Variants Tested by PharmacoScan Comments 0 By imputation Investigating the accuracy of imputation in non-caucasian populations NUDT Acute lymphoblastic leukemia patients at St. Jude tested for 4 variants on custom testing panel SCN1A 0 3 Carbamazepine and phenytoin RYR Inhaled anesthetics (desflurane, isoflurane, CACNA1S 0 1 sevoflurane) Succinylcholine NAT Isoniazid

114

Example of CDS alert algorithm from tricyclic antidepressant guideline (PMID: 27997040); see publication for detailed example

115 Example of CDS alert algorithm from tricyclic antidepressant guideline (PMID: ); see publication for detailed example alert language, corresponding to each circled number, that can be incorporated into interruptive pre-test and post-test alerts.

116 Trigger Condition 2 Flow Chart Reference Point a CDS Context, Relative to Genetic Testing No CYP2C19 result on file e 1 Pre-Test CYP2C19 Ultrarapid Metabolizer or Rapid Metabolizer 2 Post-Test CYP2C19 Normal Metabolizer 3 Post-Test CYP2C19 Intermediate Metabolizer 2 Post-test Likely CYP2C19 Intermediate Metabolizer 2 Post-test Likely CYP2C19 Poor Metabolizer 2 Post-Test CYP2C19 Poor Metabolizer 2 Post-Test CDS Alert Text b CYP2D6 and CYP2C19 genetic status may be predictive of an adverse reaction or poor response to this medication due to altered drug metabolism. Neither a CYP2D6 nor CYP2C19 genotype appears to have been ordered for this patient. Use of an alternative agent may be recommended. Please consult a clinical pharmacist c for more information. CYP2D6 and CYP2C19 genetic status may be predictive of an adverse reaction or poor response to this medication due to altered drug metabolism. This patient is predicted to be a CYP2C19 [ultrarapid/rapid] metabolizer and may be at an increased risk of a sub-optimal response. Consider selecting an alternative drug not metabolized by CYP2C19. If amitriptyline is warranted utilize therapeutic drug monitoring to guide dose adjustments. A CYP2D6 genotype does not appear to have been ordered for this patient. CYP2D6 genetic status may be important for alternative drugs. Please consult a clinical pharmacist c for more information. CYP2D6 and CYP2C19 genetic status may be predictive of an adverse reaction or poor response to this medication due to altered drug metabolism. This patient is predicted to be a CYP2C19 normal metabolizer. There is no reason to selectively adjust the dose of this medication based on the CYP2C19 result. Because a CYP2D6 genotype does not appear to have been ordered for this patient, use of an alternative agent may be recommended. Please consult a clinical pharmacist c for more information. CYP2D6 and CYP2C19 genetic status may be predictive of an adverse reaction or poor response to this medication due to altered drug metabolism. This patient is predicted to be a CYP2C19 intermediate metabolizer. There is no reason to selectively adjust the dose of this medication based on the CYP2C19 result. Because a CYP2D6 genotype does not appear to have been ordered for this patient, use of an alternative agent may be recommended. Please consult a clinical pharmacist c for more information. CYP2D6 and CYP2C19 genetic status may be predictive of an adverse reaction or poor response to this medication due to altered drug metabolism. This patient is predicted to be a likely CYP2C19 intermediate metabolizer. There is no reason to selectively adjust the dose of this medication based on the CYP2C19 result. Because a CYP2D6 genotype does not appear to have been ordered for this patient, use of an alternative agent may be recommended. Please consult a clinical pharmacist c for more information. CYP2D6 and CYP2C19 genetic status may be predictive of an adverse reaction or poor response to this medication due to altered drug metabolism. This patient is predicted to be a likely CYP2C19 poor metabolizer and may be at an increased risk of a sub-optimal response. Consider selecting an alternative drug not metabolized by CYP2C19. If amitriptyline is warranted, consider a 50% reduction of recommended starting dose e and utilize therapeutic drug monitoring to guide dose adjustments. A CYP2D6 genotype does not appear to have been ordered for this patient. CYP2D6 genetic status may be important for alternative drugs. Please consult a clinical pharmacist c for more information. CYP2D6 and CYP2C19 genetic status may be predictive of an adverse reaction or poor response to this medication due to altered drug metabolism. This patient is predicted to be a CYP2C19 poor metabolizer and may be at an increased risk of a suboptimal response. Consider selecting an alternative drug not metabolized by CYP2C19. If amitriptyline is warranted, consider a 50% reduction of recommended starting dose e and utilize therapeutic drug monitoring to guide dose adjustments. A CYP2D6 genotype does not appear to have been ordered for this patient. CYP2D6 genetic status may

117 CPIC guideline genes (n=19) and drugs, September TPMT thiopurines CYP2C19 clopidogrel CYP2C9, VKORC1 warfarin 2012 CYP2D6 codeine HLA-B abacavir SLCO1B1 simvastatin 2013 HLA-B allopurinol CYP2D6, CYP2C19 TCAs HLA-B carbamazepine DPYD -- 5FU / capecitabine TPMT thiopurines UPDATE CYP2C19 clopidogrel- -UPDATE 2014 IL28B -- PEG interferon α CFTR -- Ivacaftor G6PD -- Rasburicase CYP2C9, HLA-B -- Phenytoin CYP2D6 codeine--update HLA-B abacavir--update SLCO1B1 simvastatin UPDATE 2015 CYP3A5 tacrolimus CYP2D6, CYP2C19 SSRIs UGT1A1 atazanavir HLA-B allopurinol UPDATE 2016 CYP2C19 voriconazole CYP2D6 ondansetron CYP2C9, VKORC1 warfarin-- UPDATE CYP2D6, CYP2C19 TCAs-- UPDATE 2017 CYP2D6 tamoxifen RYR1 inhaled anesthetics CYP2B6 efavirenz TPMT/NUDT15 thiopurines--update HLA-B carbamazepine UPDATE DPYD -- 5FU / capecitabine UPDATE CYP2D6--atomoxetine

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Dosing of Mercaptopurine Based on TPMT and NUDT15 TPMT and NUDT15 Phenotype Results in EHR TPMT: Normal Metabolizer TPMT: Intermediate Metabolizer TPMT: Poor Metabolizer NUDT15: Normal or

119 Dosing of Mercaptopurine Based on TPMT and NUDT15 TPMT and NUDT15 Phenotype Results in EHR TPMT: Normal Metabolizer TPMT: Intermediate Metabolizer TPMT: Poor Metabolizer NUDT15: Normal or Intermediate Metabolizer NUDT15: Poor Metabolizer NUDT15: Normal or Intermediate Metabolizer NUDT15: Poor Metabolizer NUDT15: Any Phenotype Standard dose of mercaptopurine Dose Reduce mercaptopurine (20 mg/m 2 /day) Dose Reduce mercaptopurine (30-70% of standard dose) Dose Reduce mercaptopurine (20 mg/m 2 /day) Dose Reduce mercaptopurine (10 mg/m 2 /day given 3 days a week)

120 Utilized pharmacogenetics to safely prescribe codeine at St. Jude Normal Gammal RS, et al. Pediatrics. 2016;138(1):e

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Using Pharmacogenetic Markers in Clinical Treatment

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