Pharmakogenetik. Carlo Largiadèr. SVV Fortbildungsreihe zum Thema Genetik Olten,

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1 Pharmakogenetik Carlo Largiadèr SVV Fortbildungsreihe zum Thema Genetik Olten,

2 Aktuelle Medikamentenverschreibung Basierend auf: Zeichen und Symptomen Durchschnittlicher Wirkung Konsequenz: Ein Teil der Patienten spricht auf die Therapie an ein Teil nicht ein Teil hat schwere Nebenwirkungen Pharmakogenetik / C. Largiadèr / 28. August

3 Individuelle Wirkung von Medikamenten Genetische Faktoren Medikament Transport Umwelteinflüsse, Alter, Geschlecht andere Medikamente Medikamentenwirkung Zielmolekül Metabolismus Zelle Pharmakogenetik / C. Largiadèr / 28. August

4 Pharmacokinetics (PK) and Pharmacodynamics (PD) Pharmacokinetics is a branch of pharmacology dedicated to the determination of the fate of substances administered externally to a living organism. Pharmacodynamics is the study of the biochemical and physiological effects of drugs on the body or on microorganisms or parasites within or on the body. Mechanisms of drug action (How does the drug act at biochemical or biophysical level? E.g. influencing enzyme activity) Effect profil (Which effects occur? Which organs/structures or biological Functions are affected?) Dose response relationship, or exposure response relationship (Which doses are not effective? At what dose do we observe effects? How strongly do the effects depend on the dosing? Which doses are toxic?) =>Therapeutic window Pharmakogenetik / C. Largiadèr / 28. August 2014 wikipedia.org 4

5 Therapeutic Window ED: effective dose Individualizing Therapy is Important TD: toxic dose for Drugs with a Narrow Therapeutic Range toxicity efficacy efficacy toxicity wide therapeutic range Dose narrow therapeutic range Dose e.g. penicillin Safe to prescribe dose effective for >90% of population e.g. anticancer drug Difficult to prescribe effective non-toxic dose Pharmakogenetik / C. Largiadèr / 28. August

6 Pharmakokinetik (L)ADME Verteilung Aufnahme Liberation Freisetzung Metabolismus Absorption Aufnahme in die Blutbahn Aufnahme Distribution Verteilung im Organismus Ausscheidung Metabolism Verstoffwechselung Roche Facetten (2003) Excretion Ausscheidung (renal, biliär, pulmonal, intestinal) Pharmakogenetik / C. Largiadèr / 28. August

7 Patient specific factors Metabolism Roche Facetten (2003) Sources of PK variability Distribution Organ function Disease state Genetic regulation or differences in absorption, metabolic and excretion pathways (ADME) Circadian rhythm Age Excretion Sex Weight Absorption Uptake /Lib. Other factors Liberation the process of release of drug from the formulation. Absorption the process of a substance entering the blood circulation. Distribution the dispersion or dissemination of substances throughout the fluids and tissues of the body. Metabolism the irreversible transformation of parent compounds into daughter metabolites. Excretion the removal of the substances from the body. Mode of administration Drug drug interactions Herbal and vitamin supplements Food Patient compliance Pharmakogenetik / C. Largiadèr / 28. August

8 High inter individual PK variability Most anticancer drugs are characterised by a narrow therapeutic window; hence, a small change in dose can lead to poor antitumour effects or an unacceptable degree of toxicity Felici et al Eur J Cancer 38: Pharmakogenetik / C. Largiadèr / 28. August

9 Genetische Polymorphismen SNP Single Nucleotide Polymorphism G C T G T C A A T G C T G C T G T C A G T G C T G C T G T C A G T G C T G C T G T C A A T G C T G C T G T C A A T G C T G C T G T C A G T G C T G C T G T C A A T G C T Insertion/Deletion Gene duplication Pharmakogenetik / C. Largiadèr / 28. August

10 Genetische Polymorphismen SNP Single Nucleotide Polymorphism Insertion/Deletion Gene duplication More copies => more product Pharmakogenetik / C. Largiadèr / 28. August

11 Universitätsinstitut für Klinische Chemie Genetische Variabilität des Menschen ca. 3,2 Milliarden Basenpaare < 2% codieren für Proteine Gene Pharmakogenetik / C. Largiadèr / 28. August

12 Universitätsinstitut für Klinische Chemie Genetische Variabilität des Menschen ca. 3,2 Milliarden Basenpaare < 2% codieren für Proteine Gene Menschen nur zu 99.5 % genetisch identisch (0.1% SNPs & 0.4% Copy Number Variation) durchschnittlich alle 1200 bp 1 SNP (8 SNPs in bp) > SNP in gencodierenden Regionen > 1.2 Mio SNPs in Genregionen Durchschnittlich 1 proteinverändernder SNP pro Gen Pharmakogenetik / C. Largiadèr / 28. August 2014 SNP: Single Nucleotide Polymorphism 12

13 PGx relevante Gene Drug metabolizing enzymes Drug transporters Drug target molecules *Die Cytochrome P450 (CYP) sind Hämproteine mit enzymatischer Aktivität (Oxidoreduktasen) * * Drug metabolism Phase Iand II reactions increase the water solubility of the substrates Occurs in the liver, small intestine, kidney, lung, brain, skin Evans & Relling 1999 Science Pharmakogenetik / C. Largiadèr / 28. August

14 Geographische PGx Variabilität Each gene shows a unique geographic pattern of variation Altered activity variants can reach extremely high frequencies in specific populations CYP2C9 CYP2C19 (20677 individuals, 129 populations) (23972 individuals, 146 populations) Sistonen et al Pharmacogenet Genomics Pharmakogenetik / C. Largiadèr / 28. August

15 Pharmakogenetik ( genomik) PGx PGx untersucht Einfluss von interindividuellen genetischen Variationen auf die Wirksamkeit und Nebenwirkungen von Medikamenten. Publikationen in Pubmed UA Meyer (2004) Nature Reviews / Genetics 2013 Pharmakogenetik / C. Largiadèr / 28. August

16 Pharmakogenetik ( genomik) PGx PGx untersucht Einfluss von interindividuellen genetischen Variationen auf die Wirksamkeit und Nebenwirkungen von Medikamenten. Publikationen in Pubmed UA Meyer (2004) Nature Reviews / Genetics 2013 PGx der Erfolgsfaktor für eine individualisierte Medizin (PM): Effizienz weniger Versuch und Irrtum (das richtige Medikament) Dosierung angepasst an den Metabolismus des Patienten Sicherheit weniger schwere Nebenwirkungen Pharmakogenetik / C. Largiadèr / 28. August

17 PGx Potential: Choosing the right drug Pharmakogenetik / C. Largiadèr / 28. August

18 PGx Potential: Choosing the right drug Medikamente wirken im Schnitt nur in ca. 50% der behandelten Personen! Spear et al., 2001 BMJ Pharmakogenetik / C. Largiadèr / 28. August

19 PGx Potential: Choosing the right dose BSA based chemo dosing: 5 FU exposure varies up to 100 fold Saam et al Clinical Colorectal Cancer, 10: Pharmakogenetik / C. Largiadèr / 28. August

20 PGx Potential: Vermeidung von Medikamenten Nebenwirkungen Pharmakogenetik / C. Largiadèr / 28. August

21 PGx Potential: Vermeidung von Medikamenten Nebenwirkungen 5% aller Hospitalisierungen auf Grund von Medikamentennebenwirkungen 10 20% aller hospitalisierten Patienten haben schwere Nebenwirkungen (USA: 2 Mio Fälle im Jahr 1994) 0.1 % der Spitalpatienten sterben an Nebenwirkungen (USA: Todesfälle im Jahr 1994) häufigste Todesursache bei Spitalpatienten Pirmohamed et al., 1998 BMJ Pharmakogenetik / C. Largiadèr / 28. August

22 Serious adverse drug events Reported to the Food and Drug Administration Thomas J. Moore, et al. Arch Intern Med. 2007;167(16): Pharmakogenetik / C. Largiadèr / 28. August

23 PGx-Testing: aktuelle Situation Hulot (2010) Genome Medicine, 2:13 Pharmakogenetik / C. Largiadèr / 28. August

24 PGx testing: current situation Only few PGx tests implemented in routine clinical practice Mostly retrospective analyses of toxicity cases Pharmakogenetik / C. Largiadèr / 28. August

25 PGx Tests: Lost in Translation... Discovery Association studies Verification Marker validation Functional implications Assay developement Establish assay performance characteristics Clinical validation Evaluate marker in appropriate clinical context Cost effectiveness analysis Scientific interest / Funding Time / Costs Pharmakogenetik / C. Largiadèr / 28. August

26 Wenig offizielle PGx Information Ausnahme: somatische Mutationen in der Onkologie (Targeted Therapies /Companion Diagnostics) Pharmakogenetik / C. Largiadèr / 28. August 2014 Amstutz & Carleton, Clin. Pharmacol. Ther.; 2011; 89:

27 PGx: success stories somatic mutations in cancer Companion diagnostics Heather E. Wheeler et al. Nature Reviews Genetics AOP, published online 27 November 2012; doi: /nrg3352 For some targeted cancer therapies, specific somatic mutations are predictive of treatment efficacy. Pharmakogenetik / C. Largiadèr / 28. August

28 Wenig offizielle PGx Information Ausnahme: somatische Mutationen in der Onkologie (Targeted Therapies /Companion Diagnostics) Weitgehendes Fehlen von Guidelines Was tun wenn PGx relevante Information vorliegt? Jedoch viele Situationen, wo PGx Test sinnvoll sein kann Pharmakogenetik / C. Largiadèr / 28. August 2014 Amstutz & Carleton, Clin. Pharmacol. Ther.; 2011; 89:

29 Ein Fallbeispiel Mann, 62 Jahre Chronische Lymphatische Leukämie (Chemotherapie) Symptome: Müdigkeit, Kurzatmigkeit, Fieber, Husten Diagnose: Lungenentzündung (Lobärpneumonie) Behandlung: Antibiotika, Codein gegen den Husten Am 4. Spitaltag: Koma Morphin-Werte im Blut 20-80x höher als erwartet CYP2D6 Genotypisierung zeigt eine Duplikation des Gens Ausscheidung Abbau/ Ausscheidung Gasche et al., NEJM (2004) Pharmakogenetik / C. Largiadèr / 28. August

30 Cytochrom P450 2D6 Verantwortlich für den Abbau von Fremdstoffen im Körper Abbau von ca. 25% aller Medikamente Grosse Unterschiede in der Aktivität zwischen verschiedenen Menschen Ca % der Menschen (CH) haben CYP 2D6 dupliziert (UM) Ca. 8% der Menschen (CH haben keine CYP 2D6 Enzyme (PM) Abbau zu schnell Keine Wirkung bei normaler Dosis Zu starke Wirkung bei gewissen Prodrugs Abbau zu langsam Medikamentenspiegel zu hoch bei normaler Dosis Hohes Risiko für NW Keine Wirkung bei gewissen Prodrugs Debrisoquine/4 hydroxydebrisoquine metabolic ratio Weinshilboum (2003) Pharmakogenetik / C. Largiadèr / 28. August

31 Thiopurine S methyltransferase (TPMT) TPMT catalyses the S methylation of thiopurine drugs (azathioprine, mercaptopurine, thioguanine) => inactivation Used to treat acute lymphoblastic leukaemia of childhood, inflammatory bowel disease and organ transplant recipients Weinshilboum (2003) Narrow therapeutic index; risk of lifethreatening myelosuppression Pharmakogenetik / C. Largiadèr / 28. August

32 Genotype and thiopurine dosing The Clinical Pharmacogenetics Implementation Consortium (CPIC) advocates testing for TPMT status prior to initiating thiopurine therapy, so that starting dosages can be adjusted accordingly. Body of evidence, rather than randomized clinical trials, provides the basis for most of the dosing recommendations. Relling et al., Clin. Pharmacol. Ther. 89, (2011) Pharmakogenetik / C. Largiadèr / 28. August

33 Uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) Irinotecan Carboxylesterase SN 38 (active metabolite) Antitumor activity Toxicity UGT1A1*28 SN 38G (inactive metabolite) Elimination from body Hoskins et al., J Natl Cancer Inst. 2007; 99(17): Pharmakogenetik / C. Largiadèr / 28. August

34 UGT1A1 guidelines Pre treatement screening not recommended (Recommendation of the Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group 2009) Concern that reductions in irinotecan dosage resulting from information gained through UGT1A1 genotyping may reduce tumor response and survival => other genotypes under dosed? Pharmakogenetik / C. Largiadèr / 28. August

35 UGT1A1 genotype known Reduce the starting dose of irinotecan for UGT1A1*28 homozygous patients receiving more than 250 mg/m 2. Pharmakogenetik / C. Largiadèr / 28. August

36 5FU pharmacogenetics (PGx) a simple case? Pharmacogenetic syndrome related to a single gene/enzyme: Dihydropyrimidine dehydrogenase (DPD; DPYD)? reduced activity increased half life of 5FU increased toxicity Pharmakogenetik / C. Largiadèr / 28. August

37 DPD genotype and fluoropyrimidine dosing Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines Caudle et al., Clin. Pharmacol. Ther. 89, (2013) No pre treatment screening recommended. Based on three rare DPYD variants (frequency < 1%). Pharmakogenetik / C. Largiadèr / 28. August

38 New important DPYD variant DPYD c C>G deep intronic splice variant strongly associated with 5FU toxicity (van Kuilenburg et al. 2010) N c C>G carrier frequency Country Switzerland Germany Netherlands The sensitivity to identify early onset FP toxicity in a prospective Swiss cancer patient cohort (N = 500) was substantially increased, with 15% of severe toxicities being identified by this variant alone (Fröhlich et al. Int. J. Cancer: in press) Pharmakogenetik / C. Largiadèr / 28. August

39 Clinical importance of DPYD risk variants for the prediction of early-onset fluoropyrimidine toxicity Carrier frequency % Cohort 1 (n = 111); p = Cohort 2 (n = 389); p = Combined (n = 500); p < Grade 0-1 (n = 65/216/281) Grade 2 (n = 25/122/147) Grade 3-5 (n = 21/51/72) Carrier frequency % Risk variant carriers (n = 31); p < B4 carriers (n = 23); p = 0.03 Grade 0-1 (n = 281) Grade 2 (n = 147) Grade 3 (n = 62) Grade 4-5 (n = 10) Pre therapeutic DPYD testing may prevent 20 30% of life threatening or lethal episodes of FP toxicity in Caucasian patients Frequency % p= Risk variant carriers (n = 29) Non-carriers (n = 441) 16 carriers (55%) required FP dose interventions 10 0 No FP-dose intervention (n = 356) FP-dose intervention (n = 114) Higher dose (n = 26) Same dose (n = 330) Reduced dose (n = 53) Delay due to toxicity (n = 37) Cessation due to toxicity (n = 24) FP-dose adjustment Fröhlich et al. Int. J. Cancer: in press Pharmakogenetik / C. Largiadèr / 28. August

40 In welchen Situationen sind PGx Tests sinnvoll Sinnvoll sobald abhängig vom Testresultat eine konkrete Therapieempfehlung zu erwarten ist: z.b. Medikament A oder B oder Initialdosis um 50% reduzieren Voraussetzungen bei Auftragserteilung: Fragestellung ist klar definiert. Limitationen des Test und mögliche Therapieentscheide sind bekannt PGx Test ist schnell genug! Warfarinbehandlung zur Prävention von venösen Thromboembolien CYP2C9 and VKORC1 (n = 495) Ferder et al. (2009) Journal of Thrombosis and Haemostasis, 8 Pharmakogenetik / C. Largiadèr / 28. August

41 Pharmacogenetic tests: the need for a level playing field The delivery of more personalized medicine could be accelerated by addressing the substantial differences in the level of evidence required for the inclusion of pharmacogenetic tests in treatment guidelines, drug labelling and reimbursement schemes compared with that needed for non genetic diagnostic tests. M. Pirmohamed & D. A. Hughes NATURE REVIEWS DRUG DISCOVERY VOLUME 12 JANUARY Pharmakogenetik / C. Largiadèr / 28. August

42 Pharmacogenetic tests: the need for a level playing field There is no regulatory requirement to undertake clinical trials to show that the dosing recommendations for patients with, for example, renal impairment are equivalent in terms of clinical outcomes to those for patients with normal renal function. M. Pirmohamed & D. A. Hughes NATURE REVIEWS DRUG DISCOVERY VOLUME 12 JANUARY Pharmakogenetik / C. Largiadèr / 28. August

43 Vielen Dank für Ihre Aufmerksamkeit! Pharmakogenetik / C. Largiadèr / 28. August