Clinical Pharmacogenomics: Applications to Clinical Care

Transcription

1 Clinical Pharmacogenomics: Applications to Clinical Care May 19, 2018 Amber L. Beitelshees, PharmD, MPH University of Maryland, Baltimore School of Medicine

2 Objectives Describe the current state of pharmacogenomics in clinical practice Compare and contrast preemptive and reactive pharmacogenomics testing in clinical practice Discuss the role of pharmacists in the clinical implementation of pharmacogenomics

3 One Drug Does NOT Fit All Corporate/file/pmc_case_for_personalized_medicine.pdf

4 The Era of Precision Medicine Also known as Personalized Medicine Purpose: Provide the right patient with the right drug at the right dose at the right time. Tailor medical treatment to the individual characteristics, needs, and preferences of a patient. Identify genetic or protein biomarkers that predict drug response and/or adverse effects.

5 Pharmacogenomics (PGx) Subset of personalized and precision medicine. Goal: Understand how genetic variation contributes to variability in drug pharmacokinetics, pharmacodynamics, and toxicity. Use genetic information to guide optimal drug selection and dosing to maximize efficacy and minimize adverse effects.

6 Pharmacogenetics versus Pharmacogenomics Pharmacogenetics: Study of the relationship between variations in a single gene and variability in drug disposition, response, and toxicity. Pharmacogenomics: Study of the relationship between variations in a large collection of genes (up to the whole genome) and variability in drug disposition, response, and toxicity Ann Intern Med. 2006; 145:

7 Managing Expectations Relling and Evans; Nature 2015;526:343.

8 Actionable Genotypes in Individual and Cumulative Drug-Gene Interactions Van Driest et al. CPT 2014;95:423.

9 Clinical Pharmacogenetics Implementation Consortium (CPIC) 9 Established in 2009 as a shared project between PharmGKB and the Pharmacogenomics Research Network (PGRN). Address the need for guidelines to instruct clinicians on how to modify drug therapy based on genetic information. Provide peer-reviewed, evidence-based clinical guidelines for certain gene-drug pairs. Updated every two years. CPIC guidelines are designed to help clinicians understand HOW available genetic test results should be used to optimize drug therapy. Key assumption: Clinical high-throughput and pre-emptive genotyping will become more widespread.

10 CPIC Guidelines/Updates

11 Other Evidence-Based Resources FDA Biomarker List Information can be interpreted as genetic testing required, recommended, actionable, or informative. Dutch Pharmacogenetics Working Group (DPWG) Professional society guidelines for certain gene-drug pairs. Examples: Canadian Pharmacogenomics Network for Drug Safety (e.g., carbamazepine) DHHS antiretroviral guidelines (abacavir) American College of Rheumatology (allopurinol) Clinical Genome Resource (ClinGen) Genetics and Genomics Competency Center (G2C2) 11

12 Case Presentations Life-threatening sepsis due to leukopenia arises in a 9-year-old girl after 6-MP therapy for ALL A 32 year old male develops severe hypersensitivity reaction to abacavir for treatment of HIV A 55 year old woman started on simvastatin 40 mg/day shows no decrease in LDL 1 month later and develops severe myopathy rendering her wheel-chair bound 54 yr old male with lateral ST segment elevation MI presents again 2 weeks later with stent thrombosis

13 Active Parent Drug Parent Drug (Active) Parent Drug (Active) Decreased metabolism due to genetic variant(s) Increased metabolism due to genetic variant(s) Metabolite (Inactive) Metabolite (Inactive) Decreased metabolism due to genetic variant(s) Increased plasma exposure of the active parent drug Increased pharmacologic effect and/or risk of toxicity Increased metabolism due to genetic variant(s) Decreased plasma exposure of the active parent drug Decreased pharmacologic effect

14 What about a Prodrug? Prodrug (Inactive) Prodrug (Inactive) Decreased metabolism due to genetic variant(s) Increased metabolism due to genetic variant(s) Metabolite (Active) Metabolite (Active) Decreased metabolism due to genetic variant(s) Decreased plasma exposure of the active metabolite Decreased pharmacologic effect Increased metabolism due to genetic variant(s) Increased plasma exposure of the active metabolite Increased pharmacologic effect and/or risk of toxicity

15 CASE 1: TPMT and Thiopurine Toxicity Case: 9 yo girl with acute lymphoblastic leukemia is initiated on mercaptopurine 75 mg/m 2 /day for maintenance therapy 2 weeks after starting therapy she develops severe myelosuppression (leukopenia, neutropenia, and thrombocytopenia) Subsequently she develops an infection that progresses to sepsis She survives the episode but her chemotherapy treatment has to be delayed

16 Thiopurines (e.g. mercaptopurine, azathioprine, and thioguanine) Inhibit purine synthesis (antimitotic) Immunosuppresants used for the treatment of leukemia, inflammatory bowel disease, and other immune function disorders Rarely individuals have extreme sensitivity to thiopurines Increased risk for life-threatening bone marrow suppression (leukopenia, infection, anemia), hair loss, stomach pain, diarrhea

17 Thiopurines are Inactivated by TPMT AZA 6-thioguanines (6-TGNs) cytotoxic Therefore, there is an inverse relationship between TPMT activity and TGN concentration (risk of toxicity) HPRT = hypoxanthine-guanine phosphoribosyltransferase TPMT = thiopurine S-methyltransferase

18 TPMT Activity is Inherited TPMT activity is inherited as a monogenic co-dominant trait 3 SNPs account for >90% of inactivating alleles Single Nucleotide Polymorphisms (SNPs) Phenotyping laboratory tests also available

19 TGN [6-TGN] conc TPMT Phenotypes *1/*3A *1/*1 6-TGN concentrations 1/300 *3A/*3A Dosing recommendations in Package Insert and in CPIC guidelines LL *3A/*3A (mutant) 1 in in 3, fold dose reduction HL HH *1/*3A *1/*1 (heterozygote) (wild-type) 3-14% of pts 86-97% of pts 30-70% dose reduction Standard dose

20 CASE 2: Abacavir Hypersensitivity A 32 year old male develops severe hypersensitivity reaction to abacavir for treatment of HIV Abacavir is an HIV nucleoside analogue Approximately 5% of treated patients develop hypersensitivity syndrome [HSR] usually within 6 wks Symptoms are: skin rash, gastrointestinal and respiratory manifestations, re-challenge shock Treatment is to stop the drug early; Re-treatment with abacavir can cause severe allergic responses including anaphylactic shock Questioned whether hypersensitivity might be genetically linked, and thus predictable MHC proteins investigated b/c of known links in other immune responses Lancet 2002;359:

21 PREDICT- I : Abacavir Pgx Randomized Controlled Trial ABC-containing regimen HSR monitoring according to Standard of Care ABC-naïve Subjects N=~1800 Randomize (1:1) ABC-containing regimen HSR monitoring according to Standard of Care plus HLA-B*5701 screening 6-Week Observation Period (covers 94% of HSR cases) Exclude Subjects with positive screens Enroll Subjects with negative screens Mallal S. New Engl J Med 2008;358:568.

22 Incidence (%) PREDICT- I Results OR 0.40 (0.25, 0.62) P < Control arm Prospective HLA-B*5701 screening arm % (66/847) 3.4% (27/803) Clinically Suspected HSR 2.7% (23/842) OR 0.03 (0, 0.18) P < % (0/802) Immunologically Confirmed HSR Mallal S. New Engl J Med 2008;358:568.

23 HLA Region and ADRs Abacavir- hypersensitivity reaction Flucloxacillin- DILI Carbamazepine- Stevens-Johnson syndrome Ximelagatran- DILI Amoxicillin-clavulanate- DILI Allopurinol- Stevens-Johnson syndrome

24 Genome-wide Association Studies (GWAS): Process of identifying novel susceptibility genes for complex diseases and traits can also be applied to pharmacogenomics

25 CASE 3: Statin-Induced Myopathy A 55 year old woman started on simvastatin 40 mg/day shows no decrease in LDL 1 month later and develops severe myopathy rendering her wheel-chair bound HMG CoA Reductase inhibitors (statins) are used to lower cholesterol Generally well tolerated, but rarely associated with muscle pain/weakness associated with elevated CK Incidence typically 1 in 1,000 at doses of mg but increases with increased doses and certain drugs

26 GWAS Simvastatin-induced Myopathy (NEJM; Aug 21, 2008) SLCO1B1

27 SLCO1B1 Encodes the organic anion transporting polypeptide OATP1B1 Mediates the hepatic uptake of various drugs, including most statins Rs in complete LD with functional rs (*5; V174A) C allele associated with increased statin concentrations and increased risk of myopathy Interestingly, C allele also associated with diminished LDL response

28 GWAS Simvastatin-induced Myopathy (NEJM; Aug 21, 2008) Myopathy cumulative risk 18% in C/Cs, 3% in C/Ts, and 0.6% in T/Ts. Population attributable risk of 60% Population genotype frequencies TT = 73% CT = 24.9% CC = 2.1%

29 My Results Gene Diplotype Summary Flag Relevant Alleles Common Name Re fer Va en ria ce nt Ba Ba se se Genotype Call Change for Variant dbsnp cdna change rsnumber SLCO1B1 *1a/*1b *17 *17,*21 SLCO1B1*17_c G>A(Promoter) G A G/G Ref/Ref Promoter G>A rs SLCO1B1 *1a/*1b *2 *2,*12 SLCO1B1*2_c.217T>C(F73L) T C T/T Ref/Ref F73L 217T>C rs SLCO1B1 *1a/*1b V82A *3,*13 SLCO1B1_c.245T>C(V82A) T C T/T Ref/Ref V82A 245T>C rs SLCO1B1 *1a/*1b N130D *1b,*14,*15,* 17,*18,*21 SLCO1B1*1B_c.388A>G(N130D) A G A/G Ref/Var N130D 388A>G rs SLCO1B1 *1a/*1b *16 *16 SLCO1B1*16_c.452A>G(N151S) A G A/A Ref/Ref N151S 452A>G rs SLCO1B1 *1a/*1b *4 *4,*14,*18 SLCO1B1*4_c.463C>A(P155T) C A C/C Ref/Ref P155T 463C>A rs SLCO1B1 *1a/*1b *3 *3,*13 SLCO1B1*3_c.467A>G(E156G) A G A/A Ref/Ref E156G 467A>G rs SLCO1B1 *1a/*1b *5 *5,*15,*17 SLCO1B1*5_c.521T>C(V174A) T C T/T Ref/Ref V174A 521T>C rs SLCO1B1 *1a/*1b *18 *18 SLCO1B1*18_c.578T>G(L193R) T G T/T Ref/Ref L193R 578T>G rs SLCO1B1 *1a/*1b *6 *6 SLCO1B1*6_c.1058T>C(I353T) T C T/T Ref/Ref I353T 1058T>C rs SLCO1B1 *1a/*1b *7 *7 SLCO1B1*7_c.1294A>G(N432D) A G A/A Ref/Ref N432D 1294A>G rs SLCO1B1 *1a/*1b *8 *8 SLCO1B1*8_c.1385A>G(D462G) A G A/A Ref/Ref D462G 1385A>G rs SLCO1B1 *1a/*1b *9 *9 SLCO1B1*9_c.1463G>C(G488A) G C G/G Ref/Ref G488A 1463G>C rs SLCO1B1 *1a/*1b *10 *10,*12 SLCO1B1*10_c.1964A>G(D655G) A G A/A Ref/Ref D655G 1964A>G rs SLCO1B1 *1a/*1b *11 *11,*13 SLCO1B1*11_c.2000A>G(E667G) A G A/A Ref/Ref E667G 2000A>G rs SLCO1B1 *1a/*1b N SLCO1B1_c.571T>C(L191L) T C T/C Ref/Var L191L 571T>C rs SLCO1B1 *1a/*1b N SLCO1B1_c.597C>T(F199F) C T C/T Ref/Var F199F 597C>T rs SLCO1B1 *1a/*1b P336R P336R SLCO1B1_c.1007C>G(P336R) C G C/C Ref/Ref P336R 1007C>G rs

30 Simvastatin Dosing Recommendations Rs T/T (*1/*1): Normal myopathy risk; prescribe desired starting dose and monitor as usual Rs T/C (*1/*5, *1/*15, *1/*17): Intermediate myopathy risk; prescribe lower dose or consider alternate statin (eg pravastatin or rosuvastatin); routine CK surveillance Rs C/C (*5/*5, *5/*17, *17/*17, *15/*15, *5/*15, *15/*17): High myopathy risk; prescribe lower dose or alt statin; routine CK surveillance CPIC Guidelines

31 CASE 4 Anti-platelet agent Effective (with aspirin) for prevention of MI and stroke, and thrombosis prevention coronary stent placement and angioplasty In 2011, world s 2nd highest selling drug U.S. sales $6.7 billion Clopidogrel 54 yr old male with lateral ST segment elevation MI presents again 2 weeks later with stent thrombosis Acts by binding to ADP receptors on platelets, preventing platelet aggregation and thrombosis Great variability in response to clopidogrel 4-32% of individuals are resistant

32 The Amish Pharmacogenomics of Antiplatelet Intervention (PAPI ) Study 600 healthy Amish individuals Treated with clopidogrel for 7 days; aspirin added on day 7 Platelet aggregation studies preclopidogrel, post-clopidogrel, and postclopidogrel plus aspirin

33 Distribution of clopidogrel response Clopidogrel works in the population but not in all individuals Heritability of clopidogrel response = 0.7 GWAS with Affy 500k array

34 Genome-wide Association Study of Clopidogrel Response (ADP-stimulated platelet aggregation after clopidogrel treatment) Shuldiner et al JAMA 2009;302:849

35 CYP2C19*2 Loss of Function Variant Is a Major Determinant of Clopidogrel Response 33% CYP2C19 genotype accounts for 12% of the variation in clopidogrel response Shuldiner et al JAMA 2009;302:849

36 Event-Free Survival in Patients Treated With Clopidogrel Following PCI Stratified by CYP2C19*2 Genotype Shuldiner et al JAMA 2009;302:849

37 CYP2C19 Genotyping in the Real-World Cavallari LH, et al. JACC Cardiovasc Interv 2018;11(2):181.

38 26 Types of PGx Testing Targeted, reactive testing ( Just-in-Time ): Conduct pertinent genetic testing as a medication is prescribed. Disadvantages: Delay in obtaining results; Cost. Pre-emptive testing ( Just-in-Case ): Conduct genetic testing on many pharmacogenes at one time and store the information electronically for future use. Disadvantages: EMR capable of securely housing and disseminating information; Clinical decision support.

39 What is the Pharmacist s Role? ASHP Statement on the Pharmacist's Role in Clinical Pharmacogenomics Pharmacists have a fundamental responsibility to ensure that pharmacogenomic testing is performed when needed and that results are used to optimize medication therapy. all pharmacists should have a basic understanding of pharmacogenomics in order to provide appropriate patientcare recommendations. ASHP advocates inclusion of pharmacogenomics and its application to the therapeutic decision-making process in college of pharmacy curricula Am J Health Syst Pharm 2015;72(7):579-81

40 ASHP Statement on the Pharmacist's Role in Clinical Pharmacogenomics Elements of a basic understanding of pharmacogenomics should enable pharmacists to: Recommend PGx testing to aid in drug and dose selection. Design a patient-specific medication regimen based on a patient s PGx profile. Educate patients and other health care providers on the principles of PGx and indications for testing. Communicate PGx-specific medication recommendations to the health care team. Am J Health Syst Pharm 2015;72(7):579-81

41 PharmGKB Resources CPIC IGNITE- SPARK toolbox Genetics and Genomics Competency Center (G2C2)