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Dott. Davide Seripa Biologo Dirigente di Ricerca Laboratorio di Gerontologia-Geriatria ISTITUTO DI RICOVERO E CURA A CARATTERE SCIENTIFICO Ospedale “Casa.

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Presentazione sul tema: "Dott. Davide Seripa Biologo Dirigente di Ricerca Laboratorio di Gerontologia-Geriatria ISTITUTO DI RICOVERO E CURA A CARATTERE SCIENTIFICO Ospedale “Casa."— Transcript della presentazione:

1 Dott. Davide Seripa Biologo Dirigente di Ricerca Laboratorio di Gerontologia-Geriatria ISTITUTO DI RICOVERO E CURA A CARATTERE SCIENTIFICO Ospedale “Casa Sollievo della Sofferenza” Opera di San Pio da Pietrelcina San Giovanni Rotondo (FG) Farmacogenetica e farmacogenomica nell’anziano

2 In VI century B.C. Pythagoras reported that the adverse reaction to the ingestion of fava beans was attributable to a inter-individual differences! Ad personam optimization of drug treatments

3 1866:Mendel establishes rules of heredity. 1959:Vogel coins the term pharmacogenetics (how genetics may influence drug response). 1962:Kalow publishes the first monograph on pharmacogenetics. 1987:First nomenclature of Cytochrome P450 (CYP) gene superfamily. 1988:Gonzalez and Meyer collaborate to clone CYP2D6 and characterize the genetic defect of the debrisoquine/sparteine polymorphism. 1997:The term pharmacogenomics first appears in the literature. 2003:The human genome sequence was completed. (Meyer, Nature Rev Genet 2004;5:669-676)


5 Future prospects for pharmacogenetics in the quest of personalized medicine (Howland, J Psychosoc Nurs Ment Health Serv 2012;50:13-16) The potential role of genome and its mechanism of maintenance, interactions and modifications in pharmacogenetics and adverse drug reactions is immense… but immense is complexity than assessing the role of a SNP.

6 Pharmacogenomics: challenges and opportunities (Roden, Ann Internal Med 2006;145:749-757) Small effect Large effect Single geneWhole genome Small number of genes Great number of genes Pharmacogenetics Pharmacogenomics We are here!

7 Evolution of the Cytochrome P450 (CYP) gene superfamily La vita conquista l’ambiente terrestre Gli animali diventano erbivori, assumono tossine vegetali, e muoiono. Innesco della pressione selettiva Duplicazione dei 3 geni CYP ancestrali

8 CYP3A3 CYP3A4 CYP3A5 CYP3A5P1 CYP3A5P2 Chromosome 7 CYP2C8 CYP2C9 CYP2C18 CYP2C19 Chromosome 10Chromosome 22 CYP2D6 CYP2D7P CYP2D8P Evidence for the evolution of CYP gene superfamily by gene duplications

9 CYP3A4 20 allele families / 41 alleles CYP2D6 73 allele families / 120 alleles CYP2C9 34 allele families / 41 alleles. CYP2C19 26 allele families / 32 alleles. Variability of the CYP gene superfamily

10 (*) Human Cytochrome P450 (CYP) Allele Nomenclature Committee ( Nomenclatura per gli alleli (isoenzimi) del Citocromo P450 (CYP) secondo il Comitato Internazionale per la Nomenclatura degli alleli del Citocromo 450 (*) Maggiori famiglie geniche del CYP Famiglia CYP1:CYP1A1; CYP1A2; CYP1B1 Famiglia CYP2:CYP2A6; CYP2A13; CYP2B6; CYP2C8; CYP2C9; CYP2C19; CYP2D6; CYP2E1; CYP2F1; CYP2J2; CYP2R1; CYP2S1 Famiglia CYP3:CYP3A4; CYP3A5; CYP3A7; CYP3A43 Famiglia CYP4:CYP4A11; CYP4A22; CYP4B1 Nomenclature of the CYP gene superfamily CYP  Citocromo P450 (superfamiglia genica) 2  Questo numero identifica la famiglia del gene D  Questa lettera identifica la sottofamiglia del gene 6  Questo numero identifica il gene specifico (l’isoenzima proteico) *  Tutto quello dopo l’asterisco riguarda l’identificazione dell’allele 4  Questo numero identifica la famiglia allelica A  Questa lettera identifica l’allele specifico

11 Is not a chance if most of drugs currently used in clinical practice are lipofilic compound derived from plant metabolites, and if about 80% of these drugs are metabolized by the CYP system. Substrates of the CYP gene system

12 01234 Association between CYP2C9 genetic variants and warfarin-related outcomes 1.40 2.39 1.8 CYP2C9*3 (I359L) (Lindh, Clin Pharm Ther 2005) 2.2 CYP2C9*2 (R144C) (Higashi, JAMA 2002) CYP2C9 *1/*1 wild type 2.57 CYP2C9*2 or *3 (R144C or I359L) (Margaglione, Thromb Haemost 2000) CYP2C9*3 (I359L) (Higashi, JAMA 2002) CYP2C9*2 (R144C) (Lindh, Clin Pharm Ther 2005) Severe bleeding Risk of bleeding No bleeding

13 Vitamin K Oxide Reductase Complex 1 (VKORC1) polymorphisms and warfarin dose (Rieder, NEJM 2005;352: 2285-93) A = low-dose haplotype group B = high-dose haplotype group

14 A genome-wide association study confirms VKORC1, CYP2C9 and CYP4F2 as principal genetic determinants of warfarin dose The first genome-wide association study (GWAS) on 1053 Swedish subjetcts (325.997 SNPs). The results were confirmed in 588 additional swedish patients (p < 0.0029) (Takeuchi, PLos Genet 2009;5:e1000433) CYP2C9 and VKORC1 genotypes explain about 30-40% of the total variation in the final warfarin dose

15 The International Warfarin Pharmagenetics Consortium Estimation of the warfarin dose with clinical and pharmacogenetic data (New Engl J Med 2009;361:753-764) Derivation cohort = 4043 subjects Validation cohort = 1009 subjects

16 Warfarin genotyping reduces hospitalization rates (Epstein, J Am Coll Cardiol 2010;55:2804-2812) ~ 900 patients with information on CYP2C9 and VKORC1 available to prescribing physicians versus historical control group 6 months after the initiation of warfarin therapy, hospitalizations for hemorrhage were 28% less common in the intervention than in control group

17 Association of Cytochrome P4502C19 genotype with the antiplatelet effect and clinical efficacy of Clopidogrel (Shuldiner, JAMA 2009;302:849-858) rs12777823 polymorphism CYP2C19*2 variant in 227 patients undergoing percutaneous coronary intervention treated for 1-year with clopidogrel p=0.02 p=0.02; HR=2.42,95%CI 1.18-4.99

18 0.21234 Reduced-function CYP2C19 genotype and risk of adverse outcomes in patients treated with clopidogrel (Mega, JAMA 2010;304:1821-1830) 1.55 Meta-analysis of 9 studies evaluating 9685 patients (91.3% with PIC and 54.5% with acute coronary syndrome) 1.76 2.67 3.97 Risk of stent thrombosis CYP2C19*2/*2 CYP2C19*1/*2 CYP2C19*2/*2 CYP2C19*1/*2 Risk of CV, MI or stroke

19 February 2010 The FDA revised the label on Warfarin providing genotype-specific ranges of doses and suggesting that genotypes be taken into consideration when the drug is prescribed. The FDA added a boxed warning to prescribing information for clopidogrel: “persons with a CYP2C19 variant encoding a form of the enzyme associated with a low rate of metabolism might require dose adjustment or the use of a different drug” FDA Drug Safety Communication (Available at URL

20 I FANS e l’emorragia gastroduodenale CYP2C9 genotyping may identify subgroups of persons who potentially are at increased risk of gastroduodenal bleeding when treated with NSAIDs metabolized by CYP2C9. Reclutati (n = 78) Bleeding (n = 26) No bleeding (n = 52) AlleleSNP-IDDNA changeProtein changeEnzyme activity CYP2C9*2rs1799853C 430  TArg 144  CysDecreased CYP2C9*3rs1057910A 1075  CIle 359  LeuDecreased

21 p = 0.034 OR = 4.2 (1.1 - 16.2) Reference p < 0.001 OR = 15.8 (1.1 - 16.2) I FANS e l’emorragia gastroduodenale

22 1)Lo SNP rs1080985 nel gene CYP2D6 può influenzare l’efficacia clinica del donepezil in pazienti con malattia di Alzheimer di grado lieve/moderato. 2)L’analisi dei genotipi del CYP2D6 può essere utile per identificare sottogruppi di pazienti con differente risposta terapeutica. Il donepezil nel trattamento dell’Alzheimer Mantenimento o miglioramento dello stato cognitivo (valutato tramite ADAS-Cog e MMSE) Miglioramento dello stato funzionale (valutato tramite ADL o IADL)

23 Inibitori del CYP2D6 Fenocopia (rispetto EM) Induttori del CYP2D6 Fenocopia (rispetto EM) FortiModeratiDeboli BupropionDuloxetineAmiodaronePMDexamethasoneUM FluoxetineSertralineCimetidinePMRifampinUM ParoxetineTerbinafinePM QuinideinePM Fenocopia Un fenotipo che somiglia ad un fenotipo genetico ma che ha cause ambientali. Le fenocopie

24 Multicenter, 415 AD patients, donepezil 10mg/day, 6 months follow-up Responders = 172; Non-responders = 243 ----- Multivariate analysis corrected for age, gender, MMSE at baseline, APOE-ε4 status. Results confirm the association between rs1080985 and response to donepezil after 6 months of treatment p < 0.05; OR 1.74, 95% CI 1.01-3.00 Replication study confirm the role of CYP2D6 polymorphism rs1080985 on donepezil efficacy in Alzheimer’s disease patients (Albani, J Alzheimers Dis 2012;30:745-749)

25 Il donepezil nel trattamento dell’Alzheimer Da 552 pazienti arruolati nello studio sono stati selezionati 37 responders e 19 non-responders p = 0.005; OR = 6.286 (1.828 - 21.667). Potenza dell’analisi = 84.87%.

26 Pharmacogenomic protocols in CNS disorders and dementia (Cacabelos, Neurodegenerative Dis 2010;7:167-169) These data clearly indicate that the incorporation of pharmacogenomic protocols to dementia reserach and clinical trials can foster therapeutics optimization by helping to develop cost-effective pharmaceuticals and improve drug eccicacy and safety About 25% of the 100 most prescribed drugs in USA and western countries are psychotropic drugs currently used in dementia. A trigenic cluster integrating CYP2D6+CYP2C19+CYP2C9 polymorphic variants yealds 82 different genetic profiles in wich only 26% are normal (EM).

27 Pharmacogenetics of risperidone and haloperidol CYP2D6 genotype and plasma concentration of psychotropic drugs RISPERIDONE (Scordo, Psychopharmacology 1999;147:300-305) p<0.01 HALOPERIDOL (Bertilsson, Br J Clin Pharmacol 2002;53:111-122)

28 Defining the opportunity for pharmacogenetic intervention in primary care (Grice, Pharmacogenomics 2006;7:61-65) 607 patients in primary care (USA), 16 drugs cause ADRs 28.6% took > 1 of pharmacogenetic ADR-associated drugs Risk factors for ADRs: - Old age (p<0.001); Chronic disease (p<0.001); Number of drugs (p<0.001)

29 Farmacogenetica dell’analgesia post-operatoria - protocolli terapeutici - Lieve L1 L2 Moderato M1 M2 GraveG Dolore post-operatorio Protocollo terapeutico L1L2M1M2G ArtrosileneXXXXX ZantacXXXXX ContramalXXXXX PlasilXXXXX Fentanest---A volte- Morfina----X 40 pazienti consecutivi in terapia antidolorifica post-operatoria

30 Farmacogenetica dell’analgesia post-operatoria - protocolli terapeutici, farmaci e citocromi -

31 EM versus IM: p = 0.015 – EM versus PM: p = 0.024 – IM vs PM: p < 0.001 Farmacogenetica dell’analgesia post-operatoria - risposta terapeutica e fenotipo metabolico -

32 Farmacogenetica dell’analgesia post-operatoria - considerazioni - 1.La sovrapposizione di substrati suggerisce che, probabilmente, in questi protocolli terapeutici non si ottiene una piena azione dei diversi farmaci (come se venissero usati singolarmente!). 2.La concomitante presenza di un azione inibitoria dei substrati verso l’enzima suggerisce un ulteriore diminuzione dell’azione dei diversi farmaci. 3.Visto che i protocolli terapeutici differiscono solo per il dosaggio dei diversi farmaci, come è possibile valutare con accuratezza l’effetto terapeutico dei diversi protocolli? 4.Queste considerazione suggeriscono con forza: a)L’impiego di un farmaco principale che non abbia una concomitante azione inibitoria per l’enzima; b)L’impiego di farmaci secondari che non presentino una sovrapposizione dei substrati con il farmaco principale. 5.In questo caso si otterrebbe: a)Una piena azione farmacologica; b)La possibilità di identificare e studiare in maniera inequivocabile la risposta al trattamento terapeutico, incluse le reazioni avverse.

33 0.21357 Risk of sudden death from cardiac causes according to use of CYP3A4 inhibitors and antibiotics in 1476 cases (Ray, New England J Med 2004;351:1089-1096) Erythromycin 1.79 1.48 5.35 CYP3A4 INHIBITORS (nitroimidazole antifungal agents, diltiazem, verapamil, troleandomycin) Amoxicillin Erythromycin + CYP3A4 inhibitors

34 ?? ? I II 12 1 CYP2D6*1/*XN 2 Although CYP2D6 metabolizes paracetamol into NAPQI (N-acetyl-p-benzoquinone imine) to a lesser extent than other P450 enzymes, its activity may contribute to paracetamol toxicity in extensive and ultrarapid metabolizers. Pharmacogenetics of acetaminophen

35 Challenges and measures in PGx development (Gurwitz, Public Health Genomics 2009; 12: 134-41) Public Health Genomics Pharmacogenetics in Europe: Barriers and Opportunities European Commission Joint Research Center


37 Current Drug Metabolism 2011:12;621-634 Pharmacogenetics in Geriatric Medicine: Challenges and Opportunities for Clinical Practice Alberto Pilotto, Francesco Panza, and Davide Seripa In clinical practice several factors may explain the variable response to drug treatments, including functional and cognitive disabilities, malnutrition, organ- specific failures, concomitant diseases, and concomitant therapies. This may seriously limiting the pharmacogenetic approach to drug prescription. Geriatric patients need a multidimensional approach to optimize their clinical care including treatments. The introduction in clinical practice of pharmacogenetics may be useful to improve the “clinical decision making” in drug treatments. PHARMACOGENETICS AS A “DOMAIN” OF THE MULTIDIMENSIONAL ASSESSMENT La farmacogenetica nella clinica geriatrica - prospettive future-


39 Davide Seripa ( Laboratorio di Gerontologia-Geriatria Sig.ra Carolina Gravina Sig.ra Maria Urbano Dott.ssa Giulia Paroni Dott.ssa Grazia D’Onofrio Dott. Alberto Pilotto U.O.C. di Geriatria Dott. Antonio Greco Laboratorio Analisi Cliniche Dott. Lazzaro Di Mauro Sig.ra Antonietta P. Gallo Rianimazione 1 Dott.ssa Paola Latina U.O.C. Neurologia Policlinico Universitario “A. Gemelli” Prof. Carlo Masullo Dott. Antonio Daniele Istituto di Gerontologia e Geriatria Università degli Studi di Perugia Prof.ssa Patrizia Mecocci

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