Personalisierte Pharmakotherapie - Vereinigung Zuercher Internisten

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Personalisierte Pharmakotherapie - Vereinigung Zuercher Internisten

Personalisierte PharmakotherapieGerd Kullak-UblickKlinik für Klinische Pharmakologie und ToxikologieUniversitätsspital Zürich


Pharmacotherapy success ratesBronchial asthma: 60%Cardiac arrythmia: 60%Depression: 70%Diabetes type II: 60%Migraine: 50%ACE inhibitors: 70%-blocking agents: 70%Inflammatory bowel disease: 60%Why do so many patients not respond? Can wepredict responders and non-responders? Can we„personalize“ medicine?


Pharmacotherapy: Current situationnon-responseADRpoorresponsegood responseClearly, we need to improve. Will „personalizedmedicine“ help us?


Pharmacogenomics:Hype or hope ?Genome wideapproachsingle geneapproachGene-ExpressionGWA approachNext generationsequencingThe Lancet2010the individual genomecandidatepathwayapproachSchwab et al. DMW 2011


Determinanten der ArzneimittelantwortAlterGeschlechtGenetischeFaktorenPolypharmazieArzneimittelantwortErnährungKrankheitenAlkohol


Genetische Determinanten derArzneimittelantwortPharmakokinetikPharmakodynamikKrankheits-GenotypKomorbidität


Pharmakokinetische Determinantender ArzneimittelantwortMetabolismusVerteilungAbsorptionAusscheidung


ArzneimittelmetabolismusPhase I-ReaktionenPhase II-ReaktionenArzneistoffMetabolitPhase-I-Phase-II-MetabolitCytochrom P450 (CYP)Enzyme


Genetischer Polymorphismus im Arzneimittelabbau


Arzneimittelmetabolisierende EnzymeEvans WE and Relling MV. Science 1999;286:487-91


Pharmakogenetik von CYP2D6> 70 Allele; 5 verantwortlich für 95% derVariabilitätSubstrate: u.a. Betablocker, Tamoxifen,Antidepressiva, Antipsychotika, KodeinPM Frequenz bei Kaukasiern: 7-10%PM Frequenz bei Asiaten: < 1%


Pharmakogenetik von CYP2D6multipleaktiveGenkopienkein EnzymU.A. Meyer, Nature Rev. Genet. 2004; 5: 669


CYP2D6 und Betablocker% Reduction in Post-Exercise Heart RatePMsEMsEMsPMsPMsEMsPMsEMsDrugMetoprololTimololPropranololAtenolol% metabolizedby CYP2D675>80400Lennard 1989


CYP2D6 und KodeinKodeinantitussivCYP2D6MorphinanalgetischUGTM-3-GlukuronidinaktivUGTM-6-Glukuronidaktiv


CYP2D6 und TamoxifenTamoxifenCYP2D64-OH-Tamoxifen EndoxifenCYP2D6 Langsammetabolisiererniedrigere Endoxifen-Plasmaspiegelungünstigerer klinischer Verlauf bei Mamma-Ca


CYP2D6-basierte Dosisanpassungen fürAntidepressiva und Neuroleptika


CYP2C19 SubstrateProtonenpumpeninhibitorenCyclophosphamidbei Schnellmetabolisierern:Clopidogrel- Ovariale Insuffizienz- UrotoxizitätProdrug, muss über CYP2C19 aktiviert werden25% zeigen ein geringes Ansprechen, dadurcherhöhtes Risiko für ischämische Ereignisse !


Wirkmechanismus der ProtonenpumpeninhibitorenSchubert-Zsilavecz und Stark, Pharm. unserer Zeit 2005; 3: 194


Abhängigkeit des pH im Magen (24 h) vomCYP2C19 Genotyp unter 20 mg OmeprazolT. Furuta et al., Drug Metab. Pharmocokinet. 2005; 20: 153


Clopidogrel is Converted to its ActiveMetabolite by CYP Enzymes in the LiverIrreversible inhibition ofADP receptor on plateletsClopidogrelP2Y12Active compoundIntermediate metaboliteProdrugCYP-dependentoxidationCYP1A2CYP2B6CYP2C19CYP-dependentoxidationCYP2C19CYP3A4/5CYP2B6Schömig A. N Engl J Med 2009; 361:1108 -11


Clopidogrel ResistanceClopidogrel resistance8-40%* (300 mg loading dose)ExtrinsicIntrinsic Failure to prescribe Poor compliance Variability inabsorption Body mass index Under dosing Drug-drug interactionCellular factors Number of P2Y12receptors Varying level ofresponsiveness Platelet activation viaalternate pathwaysGenetic Polymorphism ofP2Y12 receptor gene Polymorphism ofCYP3A Polymorphism ofCYP2C19Srinivasan et al. Postgrad Med J 2008Simon et al. N Engl J Med 2009*Gurbel PA. Cardiovascular Medicine 2006


Clopidogrel ResistanceClopidogrel resistance8-40%* (300 mg loading dose)ExtrinsicIntrinsic Failure to prescribe Poor compliance Variability inabsorption Body mass index Under dosing Drug-druginteractionCellular factors Number of P2Y12receptors Varying level ofresponsiveness Platelet activation viaalternate pathwaysGenetic Polymorphism ofP2Y12 receptor gene Polymorphism ofCYP3A Polymorphism ofCYP2C19Srinivasan et al. Postgrad Med J 2008Simon et al. N Engl J Med 2009*Gurbel PA. Cardiovascular Medicine 2006


Clopidogrel Exposure in Correlation toGenotype30P = 0.01050P = 0.012Clopidogrel C max (ng/ml)2010NS P = 0.047Clopidogrel AUC (ng/ml)40302010NSNS0homoEMs heteroEMs PMs0homoEMs heteroEMs PMsCYP2C19 genotypeCYP2C19 genotypePMs = Poor metabolizers; heteroEMs = Heterozygous extensive metabolizers; homoEMs = Homozygous extensive metabolizersKim KA. Clin Pharmacol Ther 2008;84:236-42


Platelet Inhibition in Correlation toGenotypeInhibition of platetel aggregation (%)100806040200Clopidogrel 75 mg/dhomoEMsheteroEMsPMs1 2 3 4 5 6 7 8 9 10 11 12 13 14 15Clopidogrel 300mgTime (days)PMs = Poor metabolizers; heteroEMs = Heterozygous extensive metabolizers; homoEMs = Homozygous extensive metabolizersKim KA. Clin Pharmacol Ther 2008;84:236-42


Association between Status as a Carrier of aCYP2C19 Reduced-Function Allele and the PrimaryEfficacy Outcome in Subjects Receiving Clopidogrel12n = 1459Carriers12.1Primary efficacy outcome (%)10864hazard ratio for carriers: 1.53NoncarriersP=0.018.0200 30 90 180 270 360 450Days since randomizationMega JL et al., NEJM 2009;360:354


Pharmakogenetik-basierte Dosisanpassungenaufgrund von pharmakokinetischen UnterschiedenKirchheiner et al., Nature Rev Drug Discov 2005; 4: 639


Medikamentöse Therapie bei IBDDrugGenes associated with drug responseAzathioprine6-mercaptopurine5-aminosalicylatessulfasalazopyridinThiopurine methyltransferaseN - acetyltransferase 1N - acetyltransferase 2TPMTNAT1NAT2Glucocorticoids Glucocorticoid receptor hGRMultidrug resistance gene product 1 MDR1Infliximab(anti -TNF)Transporter of antigenic peptide 2Fc gamma receptor IIIa(V/V better response than F/F)TAP2FCGR-3A


Azathioprin6 -TGDNARNA6-Mercaptopurin6 - ThioguanineNucleotide6 - Thioinosin5‘-Monophosphat6-MMPTPMT6 - Methyl -MercaptopurinTPMT6-Methyl-MercaptopurinRibonucleotidePurin Synthese


• TPMT:Pharmakologie von Azathioprin– homozygot mutiert: 0.3% von Kaukasiern– heterozygot: ~ 11%– homozygot Wildtyp: 89%


Frequency of TPMT activity distribution in IBD patients20181614n = 240TPMT H/HFrequency [%]121086420TPMT H/L5 15 25 35 45 55 65 75 85 95TPMT activity [nmol MTG/g*Hb*h -1 ]Wusk B, Kullak-Ublick G et al., Eur J Clin Pharmacol 2004; 60: 5


TPMT deficiency leads to higher TGN levelsTGN (pmol/8 · 10 8 RBC)TPMT phenotypeKrynetski and Evans, Pharm Res 1999;16:342


Pharmakogenetik der TPMTniedrigeTPMT Akt.1/300intermediäreTPMT Akt.11%hoheTPMT Akt89%? Sehr hoheTPMT AktSchwereToxizitätHohes Risikofür ToxizitätNiedrigesRisikofür ToxizitätNiedrigesRisiko ?+Klinische Antwort-


Hypersensitivity to abacavir•An immunologically mediated hypersensitivity reactionaffecting 5 to 8% of patients during the first 6 weeks oftreatment•Symptoms include combinations of fever, rash,constitutional symptoms, gastrointestinal tract symptoms,and respiratorysymptomsthatbecomemoreseverewithcontinued dosing•Immediate and permanent discontinuation of abacavir ismandated, resulting in a rapid reversal of symptoms• Subsequent rechallenge with abacavir is contraindicated,since it can result in a more severe, rapid, and potentiallylife‐threatening reaction


Study design1956 patients infected with HIV1, not previously treatedwith abacavir980 underwent screening for HLA-B*5701:55 positive => did not receive abacavir925 negative => 858 received abacavir => 803could be evaluated for hypersensitivity reaction976 were assigned to the control group:913 received abacavir => 847 could be evaluatedfor hypersensitivity reaction


Epicutaneouspatch testingScreening eliminated immunologically confirmedhypersensitivity reaction, with a negative predictivevalue of 100% and a positive predictive valueof 47.9%


ConclusionHLA-B*5701 carriage clearly demarcateda high-risk group of patients, accountingfor approximately 6% of the population,from the remaining 94% who were at lowrisk for a hypersensitivity reaction toabacavir


Drug Induced Liver Injury (DILI)Direct cell stressParent drugReactive metaboliteMitochondrial inhibitionInitiation of immuneresponseInhibition ofrespiratory chainBakBadBaxCytochrome creleaseCaspases-8, -10Caspases-3, -6, -7ApoptosisRussmann, Jetter, Kullak-Ublick,Hepatology 2010; 52: 748-61


Mechanisms of drug-induced liver diseaseinduction of apoptosisdirect toxicity to cholangiocytesinterference withtransportersimmune-mediatedsinusoidal obstructionsyndromemitochondrial injurydirect toxicity tohepatocytesadapted from Russmann and Reichen: “Drug-induced and toxic liver disease”;in Weinstein, Hawkey, Bosch: Clinical Gastroenterology and Hepatology, Elsevier, 2005; 677-686


Flucloxacillin liver injury:HLA-B*5701 genotype is a major determinantMHC regionrs2395029[G]= HLA-B*5701• 51 DILI cases vs. 282 population controls• Odds ratio 80.6 (22.8-284.9)• the absolute risk to develop DILI with thisgenotype is only 1 in 500-1000Daly AK et al., Nature Genetics 2009; 41: 816-819


HLA associations with hepatotoxicityGene Associated allele Drug Type of studyClass IHLA-A *3303 Ticlopidine Candidate geneHLA-B *5701 Flucloxacillin GWALapatinibClass IIHLA-DRB1 *1501 Amoxicillin- Candidate geneclavulanate*1501 Lumiracoxib GWA*0701 Ximelagatran GWA / candidate geneAithal GP & Daly AK,Nat Genet 2010; 42: 650protective for augmentin !


Klinische Relevanz vonArzneimitteltransporternIntestinale AbsorptionHepatische und renale ExkretionVerteilung im ZielgewebeTherapieansprechenKrankheitsempfindlichkeit


Hepatische Statin-Aufnahme erfolgt über OATP1B1Zair ZM, Kullak-Ublick GA, Pharmacogenomics 2008; 9: 597-624


Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine


HMG CoA reductase inhibitors (statins)Simvastatin(Zocor®)Pravastatin(Selipran®)Fluvastatin(Lescol®)Atorvastatin(Sortis®)Rosuvastatin(Crestor®)Stark H. PharmuZ 2003


Sept. 1998 - October 2001 :12‘064 participants from the UK who had had a myocardial infarction80 mg simvastatin daily 20 mg simvastatin dailyblood samples:2, 4, 8 and 12 monthsthen every 6 monthscreatine kinase (CK) and alanine aminotransferase (ALT)subjects were questioned about new, unexplained muscle pain or weakness


Sept. 1998 - October 2001by Sept. 2006 :80 mg simvastatin daily 20 mg simvastatin daily49 / 6031 participants haddeveloped definite myopathy2 / 6033 participants haddeveloped definite myopathy49 / 6031 participants haddeveloped incipient myopathy6 / 6033 participants haddeveloped incipient myopathy


Sept. 1998 - October 2001by Sept. 2006 :80 mg simvastatin daily49 / 6031 participants haddeveloped definite myopathy96 controls matched for age,sex, estimated GFR, anduse/nonuse of amiodarone atbaseline49 / 6031 participants haddeveloped incipient myopathy


Results of Tests for a Trend in the Association between Myopathy andEach SNP Measured in the Genomewide Association StudyP values are shown for each SNP measured among 85 participants with myopathy and90 matched controls who were taking 80 mg of simvastatin daily. Analyses are based on316,184 of the 318,237 SNPs (99.4%) on the Sentrix HumanHap300-Duo BeadChip(Illumina). A result above the horizontal red line indicates strong evidence of anassociation (P < 5 x 10 -7 ).


OATP1B1 polymorphism:pharmacokinetics of simvastatin (acid)c521TTc521TCc521CCPasanen et al., Pharmacogenet Genomics 2006; 16: 873-9


Estimated Cumulative Risk of Myopathy Associated with Taking 80 mgof Simvastatin Daily, According to OATP1B1 rs4149056 GenotypeSEARCH Collaborative Group, N Engl J Med 2008


Pharmakogenetik in der OnkologieMonoklonale AntikörperTrastuzumab (Herceptin®) HER2-Ak *Rituximab (MabThera®) CD20 AKCetuximab (Erbitux®) k-ras Gen(darf nicht mutiert sein)Arzneimittel mit Wirkung auf tumorspezifischeSignalwegeImatinib (Glivec®)Tyrosinkinase-Inh.* HER2 = Human Epidermal GrowthFactor Receptor 2


ca. 25% der Brustkrebs-Patientinnen exprimierenvermehrt HER2/neu auf ihrer ZelloberflächeRoss et al., Am J Clin Path 2004

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