Pharmacogenetics: LabQuality Days Helsinki, February 8, Do you have your DNA passport? Prof Dr Ron van Schaik

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1 LabQuality Days Helsinki, February 8, 2018 Pharmacogenetics: Do you have your DNA passport? Prof Dr Ron van Schaik International Expert Center Pharmacogenetics Dept Clinical Chemistry - Erasmus MC Rotterdam, The Netherlands

2 Professor Pharmacogenetics Clinical Chemist (EuSpLM) Dept.Clinical Chemistry, Erasmus MC Rotterdam Director International Referencecenter Pharmacogenetics (IFCC) European Pharmaco- Genetics Implementation Consortium (chair) European Society for Pharmacogenomics & Personalized Therapy (President) PGx Working Group Personalized Med. Div. Mol Diagnostics Comm. Task Force PGx (chair) PGx Committe (chair) Dutch clinical PGx Network (chair) Mol Diagnostics Comm. (chair) Scientific board Dutch PGx Working Group

3 Pharmacogenetics DNA analysis to explain/ to predict the response of a patient to drug therapy Personalized Medicine Precision Medicine

4 Metabolism of drugs Blood Blood Cytochrome P450 enzymes Liver

5 Metabolism of drugs Drug concentration in blood Intestinal uptake Interindividual variation in drug metabolism Metabolism by the liver Slow metabolism Ultra-Rapid metabolism ADVERSE DRUG REACTIONS 5-7% of all hospitalizations is are due to Adverse Drug Reactions (Lazarou 1998). ADRs are the 5th cause of death. Therapeutic window Only 25-60% of all drugs prove to be effective in treatment SUBTHERAPEUTIC Dose Time Dose

6 CYTOCHROME P450 ENZYMES

7 Cytochrome P450 enzymes: 80% of all drugs ( Anti-depressives Clopidogrel (Plavix) Proton Pump Inhibitors CYP2C19 8% Efavirenz CYP2B6 CYP2E1 3% 4% CYP2A6 3% Oncology drugs Psychiatric drugs Cyclosporin, CYP3A4 tacrolimus & many, 36% many more Clozapine CYP1A2 11% CYP2D6 19% CYP3A % CYP2C9 16% Anti-coagulation (warfarin, acenocoumarol) CYP2D6 20% Anti-depressives Antipsychotics Beta-blockers Tamoxifen

8 CYP2D6 activity in Caucasian population Normal % Percentage of individual Ultra-rapid ~ 2-5 % Intermediate ~10-15 % Slow 5-10 % MR S CYP2D6 enzyme activity (metabolic ratio: debrisoquine 4OH debrisoquine)

9 CYP2D6 variant alleles in Caucasians: *1-*105

10 Geographic distribution of CYP2D6 gene duplication 1-2% 3.6% 7-10% 10% 20% 29%

11 Drugs that are substrate for CYP2D6 Pain codeine dextrometorfan dihydrocodeine ethylmorphine hydrocodone norcodeine oxycodone tramadol ADHD Atomoxetine (Staterra) Anti-arrhytmics aprindine encainide flecainide mexiletine N-propylajmaline procainamide propafenone sparteine Anti-dementia galanthamine nicergoline Anti-depressives amitryptyline clomipramine desipramine imipramine nortryptiline citalopram desmethylcitalopram fluoxetine fluvoxamine maprotiline mianserin minaprine mirtazapine paroxetine venlafaxine Antidiabetics fenformine Anti-estrogens tamoxifen Antihypertensives debisoquine guanoxan indoramin Anti-emetics dolasetron ondansetron tropisetron Anti-histaminics mequitazine promethazine Appetite inhibitors dexfenfluramine Antipsychotics haloperidol perphenazine risperidon thioridazine zuclopenthixol See also: ß - blockers alprenolol bufuralol bunitrolol bupranolol carvedilol metoprolol propanolol timolol Ca-antagonists perhexiline MAO inhibitors amiflamine brofaromine Drugs methoxyamfetamine MDMA, MDME cinnarizine flunarizine (Zanger et al 2003)

12 Clinical aplication Psychiatry Antidepressants & CYP2D6

13 Imipramine therapy (antidepressive) Hospitalization Start therapy 1st conc 2nd conc 3rd conc 4th conc 1 week 1 week 1 week 1 week 1 week 22:00 ~ 50% patients: dose adjustment based on drug concentration in blood Time in academic hospital: 4-6 weeks

14 IMI dose (mg/day) Imipramine dosis (mg/dag) Imipramine metabolism Paul Schenk et al 2008 Mol Psychiatry 0 n=11 n=69 n=90 n=11 CYP2C19 CYP2D6 Imipramine Desipramine 2OH-desipramine Imipramine dosis na bereiken van stabiele therapie 25% of standard dose >2 CYP2D6 SGD Active copies of CYP2D6

15 Stingl et al Mol Psychiatry 2013

16 Case Genotype: CYP2D6*1/*1xN > 3 alleles Ultrarapid Metabolizer A 63 year old male was prescibed nortiptylene in our Academic Center after no effect on several SSRIs. Again, no effect was seen of nortiptylene and plasma concentrations that were determined were low. The psychiatrist considered two options: Nortiptylene CYP2D6 a) noncompliance b) CYP2D6 ultrarapid metabolism

17 Case 2 (May 2015) A 26 year old woman has been suffering from depression since childhood. She has been treated with several antidepressants, but all leading to severe side effects. Now she is on fluoxetine, again with side effects, for which she receives additional medication Treatment Dosing Effect Action Paroxetine Standard Many side effects Stopped Clomipramine 150 mg Side effects / High plasma concentrations Stopped Nortriptyline Standard High plasma concentrations Stopped Risperidon Low Extrapyrimidal side effects Stopped Fluoxetine mg/day Side effects (itch, obsitipation, dry eyes) Antihistaminics, laxantia and eye-dropps Genotype: CYP2D6*4/*4 2 defective alleles Poor Metabolizer

18 Genotype vs non-genotype guided treatment of depression DNA Conventional guided (Hall Flavin 2013 Pharmacogenomics)

19 Clinical aplication Cardiology Metoprolol & CYP2D6

20 CYP2D6 and metoprolol Dosing Guidelines: PM: 25% of standard dose IM: 50% of standard dose UM: 250% of standard dose S-metoprolol plasma concentration (ng/ml) ( CYP2D6: EM IM PM 0

21 Clinical aplication Oncology Tamoxifen & CYP2D6

22 Breast cancer and Tamoxifen TAMOXIFEN Effective metabolite

23 CYP2D6 and disease free survival on tamoxifen Disease free period Proportion of patients 20% Normal Intermediate Slow Clin Pharmacol Ther 2018 Time (years) (Schroth et al 2009 JAMA)

24 Clinical aplication Pain Opiods & CYP2D6

25 Codeine Tramadol Codeine X CYP2D6 Morphine No pain relief UGT2B7 Morphine-glucuronide

26 Codeine Codeine Morphine Morphine CYP2D6 UGT2B7 Morphine-glucuronide

27 CYP2D6 UM

28 >160 drugs now with PGx info in the drug label

29 Where could PGx help you? % of population with variant alleles Psychiatry: Antidepressants, antipsychotics CYP2D6, 2C19, 1A2, 3A4 10% Cardiology: Clopidogrel (Plavix) CYPC19 15% Statins SLCO1B1 2% Warfarin /acenocoumarol CYP2C9, VKORC1 20% Oncology: Tamoxifen (breast) CYP2D6 10% Capecitabine / 5-FU DPYD 2% 6-mercaptopurine (ALL) TPMT 11% Irinotecan (colon) UGT1A1 15% Neurology Phenytoin CYP2C9, 2C19 20% Clobazam CYP3A4, 2C19 20% Dermatology Azathioprine TPMT 11% Pain Codeine, tramadol, oxycodon CYP2D6, OPRM1, COMT 10% Internal Medicine Azathioprine (Crohn s disease) TPMT 11% HIV Efavirenz CYP2B6 5% Abacavir HLA-B*5701 4% Organ Tx Azathioprine TPMT 11% Tacrolimus/cyclosporin CYP3A5, 3A4 20% MMF UGT1A9 12%

30 The laboratory Pharmacogenetics for improving patient care:

31 HLA-B*1502

32 Erasmus MC 2 independent platforms (of which is 1 CE-IVD) TAT 3 5 days In collaboration with hospital pharmacy/ clinical pharmaclogy CE-IVD test

33 Special considerations on quality for PGx testing? 1. 1 ml of blood is stored for allowing redoing DNA extraction and DNA analysis 2. DNA analysis is done with two different platforms (allele drop out!)

34 Allele drop out No mutation Primer 1 No mutation Primer 1 Primer 2 x Primer 2 Primer 1 Mutation x Primer 2 Primer 1 Mutation x Primer 2 Outcome: heterozygous Outcome: homozygous mutant

35 HOW SERIOUS A PROBLEM IS THIS?

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37 Fluoropyrimidines and DPD Capecitabine Fluoropyrimidines: 5-fluorouracil (5-FU) and capecitabine Widely used (e.g. colorectal cancer, breast cancer) ~10-30% of patients develop severe (grade 3) toxicity Diarrhea, mucositis, hand-foot-syndrome 5-FU 10-20% Excretion (urine) This results in hospitalization or suboptimal treatment ~1% of patients develop fatal toxicity >80% DPD 1-5% Dihydropyrimidine dehydrogenase (DPD) DPD plays a key role in fluoropyrimidine metabolism DPD deficiency occurs in 3-5% of the population Associated with increased risk of severe/fatal toxicity Upfront screening and dose individualization can improve patient safety DHFU (inactive) Cytotoxicity: DNA incorporation and damage Active metabolites Toxicity (slide courtesy of Linda Henricks - NKI)

38 PROSPECTIVE STUDY DPYD*2A genotype-guided dosing of fluoropyrimidines Deenen et al. J Clin Oncol 2016 (slide Linda Henricks) SYSTEMATIC REVIEW OF THE LITERATURE Patients who have DPYD*2A variant (heterozygous) N = 48 73% Patients screened for DPYD*2A variant n = 2035 (1631 treated) Patients who have DPYD*2A variant (heterozygous) N = 18 (1.1%) Patients without DPYD*2A variant N = 1613 (99%) Treated with full dose 50% dose reduction of 5-FU / capecitabine 28% Treated with normal dose (standard of of care) 23% P = P =

39 Here is my sequence (The New Yorker, 2000) Dutch Pharmacy PGx working group: Evidence-based dosing guidelines per genotype for > 60 drugs Rating evidence: Rating Clinical effect: 1 4 (RCT) A - F (death)

40 Here is my sequence (The New Yorker, 2000)

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43 Make sure you know if your patient can handle the drug you prescribe! Wishing you safe genotyping