Pharmakogenetik/-genomik als Grundlage individualisierter
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Pharmakogenetik/-genomik als Grundlage individualisierter
Christian Albrechts University Kiel University Hospital Schleswig-Holstein Institute of Experimental and Clinical Pharmacology Pharmakogenetik/-genomik als Grundlage individualisierter Therapieentscheidungen Ingolf Cascorbi 36. Interdisziplinäres Forum der Bundesärztekammer Berlin, 04.02.2012 Personalized Medicine Anwendung genomischer und molekularer Information zur • zielgerichteten Gesundheitsversorgung • Erleichterung der Entdeckung und der klinischen Testung neuer Produkte • Hilfe die Prädisposition einer Person für eine bestimmte Erkrankung oder Eigenschaft zu bestimmen" Personalized Med. 6(5) 479-480 (2009). „Classic“ concept of pharmacogenetics The observation on the polymorphic character of CYP2D6 launched numerous studies in the field of Antidepressants Neuroleptics Selected betablockers (metoprolol, carvedilol) Selected opioids (codeine, tramadol, oxycodon) Most studies aimed to determine effects on pharmacokinetics rather on the clinical outcome „Classic“ concept of pharmacogenetics Meyer UA. Nature Rev Genet 2004;5:669-676 Adaption according to standard dose (%) CYP2D6 genotype based dose adaption of antidepressents and antipsychotics 200 150 Ultra rapid 100 Fast Intermediate 50 Slow 0 Kirchheiner et al., Mol Psychiatry 2004 Clinical outcome of venlafaxine considering CYP2D6 2,5 PM ODV/V <= 0.3 EM ODV/V 1-5.2 UM ODV/V >= 5.2 2 1,5 1 0,5 0 4 64 CGI 6 4 64 6 CGI = Clinical global impression score Side effects (%) Shams et al. J Clin Pharm Ther 2006, 31:493-502 CYP2D6 poor metabolizers have more frequent side effects Laika et al. Pharmacogenomics J 2009 ADR or lack of efficay TDM Expected plasma levels Pharmacodynamic explanation? Deviating plasma levels Pharmacokinetic interaction? Genetics? yes Dose adaptation or exchange Pharmacogenetic test EM Compliance or other factors no PM or UM Dose adaptation or exchange 2001: Hype of Hope? …once researchers find the genes or molecules involved in diseases, they can work on developing medicines that target those molecules and treat the cause of the disease, not just its symptoms. WHO Definition of Genomics Genomics in health examines the molecular mechanisms and the interplay of this molecular information and health interventions and environmental factors in disease. The rise of pharmacogenetics/-genomics 1000 Pharmacogenomics Pharmacogenetics Genotyping/ sequencing/ expression analyses Publications per year 800 Phenotyping 600 400 DNA sequencing (Sanger) Invention of PCR 200 0 1960 1965 1970 1975 1980 1985 Year 1990 1995 2000 2005 2010 2007: First HapMap completed Blood coagulation Intrinsic system Extrinsic system Surface contact XII Tissue damage XIIa XI Tissue thromboplastin (III) XIa IX IXa VIIa Vitamin K dependent coagulation factors VII Ca2+ X VIII Ca2+ Phospholipoproteins Xa Ca2+ X Va Prothrombin (II) V XIII Thrombin (IIa) Phospholipids Fibrinogen XIIIa Fibrin Fibrin (instab.) (stab.) Plasminogen Fibrinopeptides Plasmin Blood and tissue activators Prospective study on CYP2C9-genotype directed warfarin dosage Caraco et al, Clin Pharmacol Ther 2007 Re-labelling of Coumadin by FDA in 2007 FOR IMMEDIATE RELEASE August 16, 2007 Media Inquiries: Karen Riley, 301-827-6242 Consumer Inquiries: 888-INFO-FDA FDA Approves Updated Warfarin (Coumadin) Prescribing Information New Genetic Information May Help Providers Improve Initial Dosing Estimates of the Anticoagulant for Individual Patients The U.S. Food and Drug Administration announced today the approval of updated labeling for the widely used blood-thinning drug, Coumadin, to explain that people's genetic makeup may influence how they respond to the drug. Manufacturers of warfarin, the generic version of Coumadin, are to add similar information to their products' labeling, FDA said. The labeling change highlights the opportunity for healthcare providers to use genetic tests to improve their initial estimate of what is a reasonable warfarin dose for individual patients. Testing may help optimize the use of warfarin and lower the risk of bleeding complications from the drug. These labeling updates are based on an analysis of recent studies that found people respond to the drug differently based, in part, on whether they have variations of certain genes. Comparisons of Warfarin Doses Predicted According to the Clinical Algorithm and the Pharmacogenetic Algorithm The International Warfarin Pharmacogenetics Consortium. N Engl J Med 2009;360:753-764 Re-labelling of Coumadin by FDA in 2010 • The patient’s CYP2C9 and VKORC1 genotype information, when available, can assist in selection of the starting dose. • In all patients, subsequent dosage adjustments must be made based on the results of PT/INR determinations. Consequences of pharmacogenomics-adapted dosing Pharmacogenetics-based maintenance dose. Individualized PGx-based 3-day initiation dose regimen followed by a PGx-based maintenance dose. Avery et al. Clin Pharm Ther 2011;90:701-706 Thrombozytenaggregationshemmung Clopidogrel ist eine Prodrug Clopidogrel-mediated inhibition of platelet aggregation is influenced by CYP2C19 Kim et al. Clin Pharmacol Ther 2008; 84, 236–242 CYP2C19 and clopidogrel response Mega et al. NEJM 2009;360:354-362 Omeprazol inhibits formation of the active metabolite of clopidogrel Anteil Tod oder rekurrentes ACS none PPI Clopidogrel + PPI Clopidogrel Consequences? Ho et al. JAMA 2009;301:937-944 Rate of TIMI major bleedings Harmsze et al. Pharmacogenet Genom 2012 (epub ahead of print) Cytochrom P450 2C19 (CYP2C19) Pharmakogenetik: Bei Patienten, die langsame CYP2C19-Metabolisierer sind, wird bei empfohlener Clopidogrel-Dosierung weniger aktiver Metabolit von Clopidogrel gebildet, was einen verminderten Effekt auf die Thrombozyten-funktion zur Folge hat. Es sind Tests verfügbar, mit denen der CYP2C19Genotyp des Patienten bestimmt werden kann. Da Clopidogrel teilweise durch CYP2C19 zu seinem aktiven Metaboliten verstoffwechselt wird, ist zu erwarten, dass der Gebrauch von Arzneimitteln, die die Aktivität dieses Enzyms hemmen, zu einem erniedrigten Spiegel des aktiven Metaboliten von Clopidogrel führt. Die klinische Relevanz dieser Wechselwirkung ist ungewiss. Als Vorsichtsmaßnahme sollte vom gleichzeitigen Gebrauch starker oder mäßig starker CYP2C19-Inhibitoren abgeraten werden … Safety Announcement [03-12-2010] The U.S. Food and Drug Administration (FDA) has added a Boxed Warning to the label for Plavix, the anti-blood clotting medication. The Boxed Warning is about patients who do not effectively metabolize the drug (i.e. "poor metabolizers") and therefore may not receive the full benefits of the drug. The Boxed Warning in the drug label will include information to: Warn about reduced effectiveness in patients who are poor metabolizers of Plavix. Poor metabolizers do not effectively convert Plavix to its active form in the body. Inform healthcare professionals that tests are available to identify genetic differences in CYP2C19 function. Advise healthcare professionals to consider use of other anti-platelet medications or alternative dosing strategies for Plavix in patients identified as poor metabolizers. Die FDA empfiehlt andere Thrombozytenaggregationshemmer oder alternative Dosierungen in CYP2C19-Poor-Metabolisierern Information on Clopidogrel Bisulfate (marketed as Plavix) [10-27-2010] The U.S. Food and Drug Administration (FDA) is reminding the public that it continues to warn against the concomitant use of Plavix (clopidogrel) and omeprazole because the co-administration can result in significant reductions in clopidogrel's active metabolite levels and antiplatelet activity… With regard to the proton pump inhibitor (PPI) drug class, this recommendation applies only to omeprazole and not to all PPIs. Not all PPIs have the same inhibitory effect on the enzyme (CYP 2C19) that is crucial for conversion of Plavix into its active form. Pantoprazole (Protonix) may be an alternative PPI for consideration. It is a weak inhibitor of CYP2C19 and has less effect on the pharmacological activity of Plavix than omeprazole. Die FDA empfiehlt Pantoprazol statt Omeprazol bei gleichzeitiger Einnahme mit Clopidogrel Holmes et al. JAMA 2011;306:2704-2714 Anwendung Pharmakogenetischer Diagnostik in der Onkologie • Überexpression bestimmter Gene im Tumor • Chromosomale Abberationen • Genetische Varianten des Tumorgenoms • Genetische Varianten des Gesamtgenoms Anwendung Pharmakogenetischer Diagnostik in der Onkologie • Überexpression bestimmter Gene im Tumor • Chromosomale Abberationen • Genetische Varianten des Tumorgenoms • Genetische Varianten des Gesamtgenoms Metabolic activation of tamoxifen Dezentje, V. O. et al. Clin Cancer Res 2009;15:15-21 Model results for disease-free survival in the unselected population and in each genotypic subgroup Aromatase (unselected) Tamoxifen CYP2D6 wt/wt Tamoxifen (unselected) Tamoxifen CYP2D6 wt/*4 Tamoxifen CYP2D6 *4/*4 Punglia et al. J. Natl. Cancer Inst. 2008;100:642-648 Schroth et al. JAMA 2009;302:1429-1436 Drug metabolizing enzymes of the liver : Phase II Drug-revelant polymorphic enzymes: • Arylamine N-acetyltransferase 2 • Thiopurine S-methyltransferase • UDP-glucuronosyltransferases Evans and Relling, Science 1999, 286:487-491 Irinotecan pathway www.pharmgkb.org Frequency of neuropenia dependent on UGT1A1 genotype adapted from Parodi 2005 Likelihood of neutropenia under irinotecan treatment UGT1A1*28/*28 UGT1A1*1/*1 and 1/*28 Hoskins et al, J Natl Cancer Inst. 2007;99:1290-5 Costs of per million basepairs of sequening At the current rate of technological progress, DNA sequencing is soon likely to become a commodity, and the generation of cheap, high quality sequence data will cease to be an issue. Craig Venter, Nature 2010;464:674 The value of phenotypic information The generation of genomic data will have little value without corresponding phenotypic information about individuals’ observable characteristics, and computational tools for linking the two. The challenges facing researchers today are at least as daunting as those my colleagues and I faced a decade ago. Craig Venter, Nature 2010;464:674 The rise of omics… …or the search for biomarkers Diagnostische Biomarker • Hohe Spezifität – Detektion von spezifischen Erkrankungen Prognostische Biomarker • Differentielle Expression – Korrelation mit Verlauf der Erkrankung • Stratifizierung von Hoch- und Niedrig-Risiko-Patienten • Orientierungshilfe für Patienteninformation und Monitoring Prädiktive Biomarker • Differentielle Expression – Korrelation mit Ansprechen der Therapie • Stratifizierung von Respondern und Non-Respondern • Orientierungshilfe zur Selektion des therapeutischen Regimes What have we learned from GWAS analyses in drug response? Confirmation of known SNPs important in warfarin PK/PD variation GWAS of statin-associated rhabdomyopathy Results of Tests for a Trend in the Association between Myopathy and Each SNP Measured in the Genomewide Association Study OATP1B1 521 T>C Confirmation of known SNP important in statin PK variation The SEARCH Collaborative Group. N Engl J Med 2008;10.1056/NEJMoa0801936 Association of OATP1B1 genotype to statin-induced rhabdomyolysis OATP1B1 521TT Statin OATP1B1 Concentration CYP3A4 Metabolite Time Association of OATP1B1 genotype to statin-induced rhabdomyolysis OATP1B1 521CC Statin OATP1B1 Concentration CYP3A4 Metabolite Time Carbamazepine-Induced Hypersensitivity Syndrome HLA-A*3101 carriers at 9-fold risk Postgrad Med J 1999;75:680-681 McCormack M et al. N Engl J Med 2011;364:1134-1143. HLA-B*5701 is associated to Abacavir hypersensitivity Abacavir nucleoside analog reverse transcriptase inhibitor Hypersensitivity: 5% of HIV patients Association to HLA-B* 5701: 48-61% Only 0-4% are HLA–B* 5701 negative HLA-B*5701 exhibits a broad interethnic variability Flucloxacillin induced liver toxicity HLA-B *5701 p = 8.7 * 10-33 Confirmation of known SNP important in flucloxacillin-related DILI 51 DILI-cases vs. 282 population controls Daly et al. Nature Genetics 2009;41:816-821 Flucloxacillin induced liver toxicity Daly et al. Nature Genetics 2009;41:816-821 Funds from the Netherlands ATLA — Alternatives to Laboratory Animals to set up a DILIGEN study University of Utrecht University of Kiel Dept. Pharmacy Dept. Pharmacology Dr. Antje-Hilse Maitland van der Zee Prof. Ingolf Cascorbi Dr. Anneke Werk Medical Practices AKdÄ Berlin Prof. Ursula Gundert-Remy Dr. Thomas Stammschulte DILI GENE Genetische Ursachen Arzneistoff-induzierter Lebertoxizität Ziel • Identifikation genetischer Risikofaktoren, die die Variabilität in der Reaktion auf die Arzneistoffe erklären helfen • Identifikation von Biomarkern, die die Diagnose arzneimittel-induzierter Lebertoxizität verbessern • Langfristig Verbesserung der Arzneimittelsicherheit • Verordnung von Arzneimitteln entsprechend den individuellen Risikofaktoren DILI GENE Genetische Ursachen Arzneistoff-induzierter Lebertoxizität Definition der DILIGENE-Studie (SAE consortium) • klinisch auffälliger Ikterus oder Bilirubin >40 µmol/l • AST > 5x ULN • AP > 2x ULN + Bilirubin > ULN Daly et al., 2009 Nature Genetics 200941:816-819 DILI GENE Genetische Ursachen Arzneistoff-induzierter Lebertoxizität iSAEC’s “Clinical Registry” Technology Integrated study management, EDC, ePRO, and CDMS for late phase observational studies & registries iSAEC Phase 2 Objectives (2010-2012 ) Balanced Investment Mix to Enable Research Goals Case Recruitment Discovery Research Academic networks iDILIC – Liver Injury ITCH – Hypersensitivity GWAS Common risk factors Existing collections Pharmacos Partners New channels EMR-based Integrated healthcare systems Resequencing Rare risk factors Mechanistic studies Pathways and context “Developing new SAE research opportunities” 58 Individualized therapy: now fact or still fiction? Drugs with Tests Required Abacavir: Before initiating treatment with abacavir, screening for carriage of the HLA-B*5701 allele should be performed in any HIV-infected patient, irrespective of racial origin. Abacavir should not be used in patients known to carry the HLA-B*5701 allele, unless no other therapeutic option is available in these patients, based on the treatment history and resistance testing (see section 4.4 and 4.8). Carbamazepine: “Before deciding to initiate treatment, patients of Han Chinese and Thai origin should whenever possible be screened for HLA-B*1502 as this allele strongly predicts the risk of severe carbamazepine-associated SJS (see section 4.4)” Drugs with pharmacogenetic tests recommended by FDA Cumadin (Warfarin): The patient’s CYP2C9 and VKORC1 genotype information, when available, can assist in selection of the starting dose In all patients, subsequent dosage adjustments must be made based on the result of PT/INR determinations. Camptosar (Irinotecan): Individuals who are homozygous for the UGT1A1*28 allele are at increased risk for neutropenia following initiation of CAMPTOSAR treatment. A reduced initial dose should be considered for patients known to be homozygous for the UGT1A1*28 allele. Heterozygous patients may be at increased risk for neutropenia. Imuran (Azathioprine): It is recommended that consideration be given to either genotype or phenotype patients for TPMT. TPMT testing cannot substitute for complete blood count (CBC) monitoring in patients receiving IMURAN Drugs with pharmacogenetic tests required Gleevec (imatinib) for c-kit+ GIST [and for Ph+ CML] Tasigna (nisotinib) for imatinib-resistant Ph+ CML Sprycel (dasatinib) for imatinib-resistant Ph+ CML Trisenox (arsenic trioxide) for PML/RARα gene+ [or t(15;17) translocation] acute promyelocytic leukemia Herceptin (HER2/neu over expression necessary for patients appropriate for therapy) Erbitux (cetuximab) for EGFR+ metastatic CRC after failure ofirinotecan; KRAS wild-type metastatic CRC Tarceva (erlotinib) for advanced NSCLC (« no clinically relevanteffects demonstrated for patients with EGFR– tumours, i.e. ≤ 10% cells ») Vectibix (panitumumab) for EGFR+, non-mutated KRAS, metastatic, previously treated CRC –conditional MA Tyverb (lapatinib) in combination with capecitabine for Her2+ BC after failure of taxanes and trastuzumab –conditional MA Iressa (gefitinib), for the treatment of adult patients with locally advanced or metastatic non-small cell lung cancer with activating mutations of EGFR-TK System Biologists Biometrician Human Genetists Microbiologists Clinical Chemists Pathologists Radiologists Clinical Pharmacologists Physician B Physician C Physician A Patient Notwendigkeit von Biomarkern für die individualisierte Behandlung Diagnostische Biomarker • Hohe Spezifität – Detektion von spezifischen Erkrankungen Prognostische Biomarker • Differentielle Expression – Korrelation mit Verlauf der Erkrankung • Stratifizierung von Hoch- und Niedrig-Risiko-Patienten • Orientierungshilfe für Patienteninformation und Monitoring Prädiktive Biomarker • Differentielle Expression – Korrelation mit Ansprechen der Therapie • Stratifizierung von Respondern und Non-Respondern • Orientierungshilfe zur Selektion des therapeutischen Regimes Vielen Dank für Ihre Aufmersamkeit