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
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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
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 Medicine
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
Meyer UA. Nature Rev Genet 2004;5:669-676
„Classic“ concept of pharmacogenetics
0
50
100
150
200
Adap
tion a
ccord
ing t
o s
tandard
dose (
%)
Ultra rapid
Fast
Intermediate
Slow
Kirchheiner et al., Mol Psychiatry 2004
CYP2D6 genotype based dose adaption of
antidepressents and antipsychotics
0
0,5
1
1,5
2
2,5
CGI Side effects (%)
PM ODV/V <= 0.3
EM ODV/V 1-5.2
UM ODV/V >= 5.2
Clinical outcome of venlafaxine
considering CYP2D6
Shams et al. J Clin Pharm Ther 2006, 31:493-502
4 64 6 4 64 6
CGI =
Clinical global impression score
CYP2D6 poor metabolizers
have more frequent side effects
Laika et al. Pharmacogenomics J 2009
ADR or lack of efficay
TDM
Deviating plasma levels Expected plasma levels
Pharmacodynamic explanation?
Genetics?
Pharmacokinetic interaction?
yes no
EM
Dose adaptation or exchange
PM or UM
Pharmacogenetic test
Dose adaptation or exchange Compliance or other factors
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.
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.
The International Warfarin Pharmacogenetics Consortium. N Engl J Med 2009;360:753-764
Comparisons of Warfarin Doses Predicted According to
the Clinical Algorithm and the Pharmacogenetic Algorithm
• 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
• 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
Academic networks
iDILIC – Liver Injury
ITCH – Hypersensitivity
GWAS
Common risk factors
Resequencing
Rare risk factors
Mechanistic studies
Pathways and context
“Developing new SAE research opportunities”
Discovery Research
Case Recruitment
New channels
EMR-based
Integrated healthcare systems
Existing collections
Pharmacos
Partners
58
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)”
Individualized therapy: now fact or still fiction?
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
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
Drugs with pharmacogenetic tests required
Patient
Physician A
Physician C Physician B
Clinical
Pharmacologists
Human Genetists
Pathologists
Clinical Chemists
Biometrician
Microbiologists
System Biologists
Radiologists
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