Two decades of clinical pharmacogenetic testing - Where do we stand?

Transcription

1 Two decades of clinical pharmacogenetic testing - Where do we stand? Marja-Liisa Dahl, MD PhD, Professor Dept of Clinical Pharmacology Karolinska University Hospital/Karolinska Institutet Stockholm, Sweden

2 Personalised Medicine - the concept of drug treatment being optimised for the individual patient on the basis of genetic predisposition clinical indication genotyping drug & dose

3 Clinical Genotyping at Karolinska 1990 CYP2D6 and CYP2C CYP2C9 TPMT pheno- and genotyping HLA-B*5701 Accredited (ISO 15189) 2010 VKORC1 M-L Dahl

4 Genotype analyses at Karolinska TPMT 700 Number of samples HLA- B*5701 CYPs M-L Dahl

5 Genotyping offered by Swedish Hospital Laboratories Linköping Göteborg Uppsala Stockholm (Lund)

6 Pharmacogenetic tests performed in Swedish health care laboratories CYP2D6 CNS drugs, tamoxifen CYP2C19 clopidogrel, certain antidepressants CYP2C9 (and VKORC1) TPMT HLA-B*5701 warfarin azathioprim, 6-mercaptopurine Abacavir NAT2 UGT1A1 MTHTR SLCO1B1 isoniazide Irinotecan Specific tumour markers in oncology, performed usually at Pathology Labs

7 Genotyping services Karolinska electronic analysis request, sample registration, results into the TDM-database, and final reports electronically incorporated into patient medical records Fully reimbursed LABINICAL DATA REQUEST CL DRUGS genes? Decision on analysis (yes/no, genes/alleles of relevance) by clinical pharmacologists who also interprets the results and finalises the report M-L Dahl

8 Clinical pharmacogenetics prospective use many patients to identify patients at increased risk of adverse drug reactions poor response to identify patients who will benefit from treatment as an aid to choise of drug and/or dose?

9 HLA-B*5701 and abacavir Abacavir first-line drug against HIV-infection Serious hypersensitivity reactions develop in around 5% of treated patients, within 6 weeks The PREDICT-1 study (NEJM, 2008) provided strong evidence for the utility of prospective HLA genotyping exclusion of HLA-B*5701 carriers from abacavir treatment markedly reduced hypersensitivity reactions

10 Polymorphic CYP enzymes examples of substrates CYP2D6 CYP2C9 CYP2C19 7% PM 1% PM 3% PM antidepressants S-warfarin proton pump antipsychotics NSAIDs inhibitors codeine phenytoin citalopram propafenone oral antidiabetics escitalopram tolterodine losartan clopidogrel tamoxifen irbesartan atomoxetine M-L Dahl

11 EM IM UM PM

12 Nortriptyline kinetics and CYP2D6 genotype (Dalén et al 1998)

13 CYP2D6 and nortriptyline dosage EM UM IM PM 500 mg mg mg

14 Nortriptyline CYP2D6 10-hydroxy-nortriptyline

15 Enzymes catalysing the metabolism of antidepressant drugs CYP1A2 CYP2D6 CYP2C9 CYP2C19 CYP3A4 Amitriptyline Amitriptyline Amitriptyline Amitriptyline Clomipramine Clomipramine Clomipramine Clomipramine Imipramine Imipramine Imipramine Imipramine Desipramine Nortriptyline Venlafaxine Venlafaxine Fluoxetine Fluoxetine Fluoxetine Paroxetine Fluvoxamine Fluvoxamine Citalopram (metab) Es/citalopram Sertralin Mianserin Mirtazapine Mirtazapine Mirtazapine Moclobemide

16 CYP2D6 and antidepressant dosing Kirchheiner et al 2004

17 CYP2D6 genotype and plasma concentrations of risperidone and its active moiety (risperidone plus 9-OHrisperidone) Scordo et al., 1999 M-L Dahl

18 Prediction of warfarin maintenance dose for a typical 50 year old patient to reach an INR of 2.5 CYP2C9 genotype *1/*1 *1/*2 *1/*3 *2/*2 *2/*3 *3/*3 VKORC1 genotype GG GA AA Hamberg A-K et al

19 Clinical pharmacogenetics prospective use many patients to identify patients at increased risk of adverse drug reactions poor response to identify patients who will benefit from treatment As an aid to choise of drug and/or dos? retrospective use - selected cases to better understand the individual case, for differential diagnosis erik.eliasson@ki.se

20 Retrospective analyses origin of requests CLINICAL OBSERVATION DRUG INFO CENTRE TDM GENOTYPING M-L Dahl

21 Case 1 Request from GP: Q: A man with chronic ischaemic pain in legs; no pain relief despite very high doses of codeine Ultrarapid metaboliser? Codeine metabolised by CYP2D6 to morphine. A: Analytical result CYP2D6*4/*4, i.e. poor metaboliser and no bioactivation of codeine to morphine. Explains the lack of pain relief.

22 Case 2 Via drug information centre: Q: A case of warfarin intoxication requiring extremely long vitamin K-treatment. What could be the explanation? A: Analytical result CYP2C9*3/*3 implying very slow elimination of warfarin. M-L Dahl

23 Case 3 from a psychiatrist: Q: A female patient with pronounced adverse effects at ordinary doses of citalopram. Poor metaboliser? Citalopram is metabolised by CYP2C19 and CYP2D6. A: Analytical results CYP2C19*1/*2 (heterozygous carrier of defect gene) in combination with CYP2D6*4/*4 (poor metaboliser). Drug and/or drug metabolite accumulation likely, TDM recommended. M-L Dahl

24 Clinical background for genotyping in CYP2D6 PM- and UM-cases (Karolinska Huddinge 97-06) PM genotype - reason for analysis (%) ADR poor resp not spec TDM only UM genotype - reason for analysis (%) ADR poor resp not spec TDM only Sjöqvist and Eliasson, Clin Pharmacol Therap 2007

25 PgX and TDM are complementary Pharmacogenetic testing + sampling any time irrespective of treatment + prospective testing possible - crude classification of subjects into few categories - does not take clinical factors into account -allele choice needs to be correct (e.g. ethnicity) TDM - Sampling time crucial - only during on-going treatment + quantitative measure of actual drug exposure + reflects relevant PK parameters (DDIs, age, renal function etc) M-L Dahl

26 Age Drug intake Diseases Genetics Pharmacokinetics Pharmacodynamics Interactions Clinical response Diet M-L Dahl

27 Drug response is a complex polygenic trait influenced by many non-genetic factors Unclear diagnosis, other diseases Genetically determined poor metabolic capacity Non-responder genotype Poor adherence Renal insufficiency Drug interactions Insufficient Adequate Adverse drug reactions Treatment outcome distribution in clinical praxis

28 Focus in the future Relevant PGX to be implemented in national/ local treatment guidelines Standardized and clear reports of genotype results and prediction of phenotype Graphic when possible! Evidence based decision support for PGX Continued education of prescribers Systematic collection of outcome data M-L Dahl

29 Thank You! M-L Dahl

30 Risperidone metabolism CYP3A4 CYP2D6

31 Antipsychotics and CYP2D6 genotype Kirchheiner et al. Molecular Psychiatry 2004 M-L Dahl

32 Olanzapine metabolism FMO CYP1A2 UGT1A4 g.142t>g, L48V (UGT1A4*3) increased glucuronidation CYP2D6 Kassahun K, Mattiuz E, et al. Drug Metab. Dispos. 1997;25(1): M-L Dahl

33 Retrospective genotyping from GP: A male with chronic ischaemic pain in legs; no pain relief despite very high doses of codeine ultrarapid metabolism? CYP2D6*4/*4, poor metaboliser, no bioactivation of codeine. from psychiatrist: A woman with pronounced adverse effects from ordinary doses of citalopram - poor metaboliser? CYP2C19*1/*2 in combination with CYP2D6*4/*4. Drug and/ or drug metabolite accumulation likely, TDM recommended. Via Drug informatopn centre: A case of self-inflicted warfarin intoxication requiring extremely long vitamin K-treatment. CYP2C9*3/*3 implying slow elimination of warfarin.

34 Induction Non-responder genotype Poor adherence Treatment outcome in clinical praxis Decreased renal function Genetically determined poor metabolic capacity Drug interactions Number of pat Insufficient effect Adequate Adverse drug reactions M-L Dahl

35 Skogh et al. 2002

36 Summary 1. Clinical pharmacogenetics prospective use, to identify patients at increased risk of serious adverse drug reactions or therapeutic failure retrospective use, to better understand the individual case, differential diagnosis 2. Today only a few examples with genetic screening of patients in clinical medicine 3. Clinical pharmacological input required for the identification of relevant clinical applications among pharmacogenetic discoveries for the interpretation of individual clinical cases

37 Number of TDM-requests per therapeutic area antibiotics 6000 antipsychotics 5000 antivirals antidepressants cardiovascular year erik.eliasson@ki.se

38 Sims et al Pharmacogenomics J 2013 M-L Dahl

39 1. Clinical pharmacogenetics prospective use, to identify patients at increased risk of serious adverse drug reactions or therapeutic failure retrospective use, to better understand the individual case, differential diagnosis 2. Today only a few examples with prospective screening of patients 3. Clinical pharmacological input required for the identification of relevant clinical applications among pharmacogenetic discoveries for the choise of relevant genotypes for the interpretation of individual clinical cases M-L Dahl

40 CYP2D6 and personality Bertilsson L et al, Lancet 1989 PM (n=51) had lower scores in the Karolinska psychasthenia scale and higher frequency of extreme responses than EM (n= 102) Low psychasthenia scores imply high vitality, alertness, efficiency and ease of decision making M-L Dahl

41 CYP2D6 and personality Associations between CYP2D6 genotype and personality found also by other groups with respect to: Cognitive & social anxiety, socialization (Llerena et al, 1993) Psychic and somatic anxiety, socialization, irritability (Gonzalez et al 2008) Impulsivity, sustained attention, overall psychopathology, neurocognition (Penas-Lledo et al, 2009) Conscientiousness in women (Kirchheiner et al, 2006) M-L Dahl

42 CYP2D6 and CNS CYP2D6 expressed in several regions of the brain CYP catalyses the biotransformation of tyramine to dopamine and the regeneration of serotonin from 5- methoxytryptamine Lower platelet serotonin levels in PM than in EM and UM Could thus influence central serotonergic activity, which in turn is associated with depressive and anxious personality dimensions M-L Dahl

43 CYP2D6 UM genotype and suicidal behaviour Inactive CYP2D6*4 alleles less frequent among cases of fatal drug intoxications than among blood donors (Zackrisson et al 2004) 10-fold higher frequency of individuals with more than 2 functional CYP2D6 alleles (i.e. UM) among suicide cases (4.7%) than among cases with natural death (0.5%) (Zackrisson et al 2010) Increased frequency of UM among patients with eating disorders showing suicidal behaviour (Penas-LLedo et al 2011) Elevated risk of high suicidality in CYP2D6 UM subjects among depressed patients (Stingl & Viviani 2011) M-L Dahl

44 Higher perfusion levels in the thalamus in PM than in EM Changes in regions associated with alertness and serotonergic function 188 healthy subjects M-L Dahl