Diapositiva 1

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Farmacogenetica e farmacogenomica nellanziano
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) http//www.operapadrepio.it
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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
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(Meyer, Nature Rev Genet 20045669-676)
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.
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Future prospects for pharmacogenetics in the
quest of personalized medicine (Howland, J
Psychosoc Nurs Ment Health Serv 20125013-16)
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.
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Pharmacogenomics challenges and
opportunities (Roden, Ann Internal Med
2006145749-757)
Small effect
Large effect
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Evolution of the Cytochrome P450 (CYP) gene
superfamily
La vita conquista lambiente terrestre
Gli animali diventano erbivori, assumono tossine
vegetali, e muoiono.
Innesco della pressione selettiva
Duplicazione dei 3 geni CYP ancestrali
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Evidence for the evolution of CYP gene
superfamily by gene duplications
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Variability of the CYP gene superfamily
CYP3A4 20 allele families / 41 alleles
CYP2D6 73 allele families / 120 alleles
CYP2C9 34 allele families / 41 alleles.
CYP2C19 26 allele families / 32 alleles.
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Nomenclature of the CYP gene superfamily
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
() Human Cytochrome P450 (CYP) Allele
Nomenclature Committee (http//www.imm.ki.se/CYPal
leles/)
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Substrates of the CYP gene system
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.
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Association between CYP2C9 genetic variants and
warfarin-related outcomes
1.40
CYP2C92 (R144C) (Higashi, JAMA 2002)
2.39
CYP2C93 (I359L) (Higashi, JAMA 2002)
1.8
CYP2C92 (R144C) (Lindh, Clin Pharm Ther 2005)
Severe bleeding
2.2
CYP2C93 (I359L) (Lindh, Clin Pharm Ther 2005)
Risk of bleeding
2.57
CYP2C92 or 3 (R144C or I359L) (Margaglione,
Thromb Haemost 2000)
No bleeding
CYP2C9 1/1 wild type
0
1
2
3
4
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Vitamin K Oxide Reductase Complex 1 (VKORC1)
polymorphisms and warfarin dose(Rieder, NEJM
2005352 2285-93)
A low-dose haplotype group B high-dose
haplotype group
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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 lt 0.0029) (Takeuchi, PLos Genet
20095e1000433)
CYP2C9 and VKORC1 genotypes explain about 30-40
of the total variation in the final warfarin dose
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The International Warfarin Pharmagenetics
Consortium Estimation of the warfarin dose with
clinical and pharmacogenetic data (New Engl J
Med 2009361753-764)
Derivation cohort 4043 subjects Validation
cohort 1009 subjects
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Warfarin genotyping reduces hospitalization
rates (Epstein, J Am Coll Cardiol
2010552804-2812)
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
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Association of Cytochrome P4502C19 genotype with
the antiplatelet effect and clinical efficacy of
Clopidogrel (Shuldiner, JAMA 2009302849-858)
rs12777823 polymorphism CYP2C192 variant in 227
patients undergoing percutaneous coronary
intervention treated for 1-year with clopidogrel
p0.02 HR2.42,95CI 1.18-4.99
p0.02
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Reduced-function CYP2C19 genotype and risk of
adverse outcomes in patients treated with
clopidogrel (Mega, JAMA 20103041821-1830)
Meta-analysis of 9 studies evaluating 9685
patients (91.3 with PIC and 54.5 with acute
coronary syndrome)
Risk of CV, MI or stroke
1.55
1.76
Risk of stent thrombosis
2.67
3.97
0.2
1
2
3
4
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FDA Drug Safety Communication(Available at URL
http//www.fda.gov/)
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
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I FANS e lemorragia gastroduodenale
Allele SNP-ID DNA change Protein change Enzyme activity
CYP2C92 rs1799853 C430?T Arg144?Cys Decreased
CYP2C93 rs1057910 A1075?C Ile359?Leu Decreased
CYP2C9 genotyping may identify subgroups of
persons who potentially are at increased risk of
gastroduodenal bleeding when treated with NSAIDs
metabolized by CYP2C9.
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I FANS e lemorragia gastroduodenale
p lt 0.001 OR 15.8 (1.1 - 16.2)
p 0.034 OR 4.2 (1.1 - 16.2)
Reference
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Il donepezil nel trattamento dellAlzheimer

1. Lo SNP rs1080985 nel gene CYP2D6 può influenzare
   lefficacia clinica del donepezil in pazienti con
   malattia di Alzheimer di grado lieve/moderato.
2. Lanalisi dei genotipi del CYP2D6 può essere
   utile per identificare sottogruppi di pazienti
   con differente risposta terapeutica.

• Mantenimento o miglioramento dello stato
  cognitivo (valutato tramite ADAS-Cog e MMSE)
• Miglioramento dello stato funzionale (valutato
  tramite ADL o IADL)

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Le fenocopie
Fenocopia Un fenotipo che somiglia ad un fenotipo
genetico ma che ha cause ambientali.
Inibitori del CYP2D6 Inibitori del CYP2D6 Inibitori del CYP2D6 Fenocopia (rispetto EM) Induttori del CYP2D6 Fenocopia (rispetto EM)
Forti Moderati Deboli Fenocopia (rispetto EM) Induttori del CYP2D6 Fenocopia (rispetto EM)
Bupropion Duloxetine Amiodarone PM Dexamethasone UM
Fluoxetine Sertraline Cimetidine PM Rifampin UM
Paroxetine Terbinafine PM
Quinideine PM
http//medicine.iupui.edu/clinpharm/ddis/table.asp
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Replication study confirm the role of CYP2D6
polymorphism rs1080985 on donepezil efficacy in
Alzheimers disease patients (Albani, J
Alzheimers Dis 201230745-749)
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-e4 status.
Results confirm the association between rs1080985
and response to donepezil after 6 months of
treatment p lt 0.05 OR 1.74, 95 CI 1.01-3.00
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Il donepezil nel trattamento dellAlzheimer
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
dellanalisi 84.87.
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Pharmacogenomic protocols in CNS disorders and
dementia (Cacabelos, Neurodegenerative Dis
20107167-169)
About 25 of the 100 most prescribed drugs in USA
and western countries are psychotropic drugs
currently used in dementia.
A trigenic cluster integrating CYP2D6CYP2C19CYP2
C9 polymorphic variants yealds 82 different
genetic profiles in wich only 26 are normal (EM).
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
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Pharmacogenetics of risperidone and haloperidol
CYP2D6 genotype and plasma concentration of
psychotropic drugs
RISPERIDONE (Scordo, Psychopharmacology
1999147300-305)
HALOPERIDOL (Bertilsson, Br J Clin Pharmacol
200253111-122)
plt0.01
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Defining the opportunity for pharmacogenetic
intervention in primary care (Grice,
Pharmacogenomics 2006761-65)
607 patients in primary care (USA), 16 drugs
cause ADRs
28.6 took gt 1 of pharmacogenetic ADR-associated
drugs Risk factors for ADRs - Old age (plt0.001)
Chronic disease (plt0.001) Number of drugs
(plt0.001)
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Farmacogenetica dellanalgesia post-operatoria-
protocolli terapeutici -
40 pazienti consecutivi in terapia antidolorifica
post-operatoria
  Protocollo terapeutico Protocollo terapeutico Protocollo terapeutico Protocollo terapeutico Protocollo terapeutico
  L1 L2 M1 M2 G
Artrosilene X X X X X
Zantac X X X X X
Contramal X X X X X
Plasil X X X X X
Fentanest - - - A volte -
Morfina - - - - X
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Farmacogenetica dellanalgesia post-operatoria-
protocolli terapeutici, farmaci e citocromi -
Artrosilene (ketoprofene) Zantac (ranitidina) Contramal (tramadolo) Plasil (metoclopramide) Fentanest (fentanile) Morfina
CYP1A2 - S I - - - -
CYP2B6 - - S - - -
CYP2C8 I - - - - S
CYP2C9 S I - - - - -
CYP2C19 - S - - - -
CYP2D6 - S I S I S I - S
CYP3A4 - I S I - S I S
CYP3A5 - I - - S -
CYP3A7 - - - - S -
CYP17A1 - - - I - -
S Substrato I Inibitore. S Substrato I Inibitore. S Substrato I Inibitore. S Substrato I Inibitore. S Substrato I Inibitore. S Substrato I Inibitore. S Substrato I Inibitore.
http//www.drugbank.ca/ http//www.drugbank.ca/ http//www.drugbank.ca/ http//www.drugbank.ca/ http//www.drugbank.ca/ http//www.drugbank.ca/ http//www.drugbank.ca/
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Farmacogenetica dellanalgesia post-operatoria-
risposta terapeutica e fenotipo metabolico -
EM versus IM p 0.015 EM versus PM p
0.024 IM vs PM p lt 0.001
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Farmacogenetica dellanalgesia post-operatoria-
considerazioni -

• 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!).
• La concomitante presenza di un azione inibitoria
  dei substrati verso lenzima suggerisce un
  ulteriore diminuzione dellazione dei diversi
  farmaci.
• Visto che i protocolli terapeutici differiscono
  solo per il dosaggio dei diversi farmaci, come è
  possibile valutare con accuratezza leffetto
  terapeutico dei diversi protocolli?
• Queste considerazione suggeriscono con forza
• Limpiego di un farmaco principale che non abbia
  una concomitante azione inibitoria per lenzima
• Limpiego di farmaci secondari che non presentino
  una sovrapposizione dei substrati con il farmaco
  principale.
• In questo caso si otterrebbe
• Una piena azione farmacologica
• La possibilità di identificare e studiare in
  maniera inequivocabile la risposta al trattamento
  terapeutico, incluse le reazioni avverse.

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Risk of sudden death from cardiac causes
according to use of CYP3A4 inhibitors and
antibiotics in 1476 cases (Ray, New England J Med
20043511089-1096)
CYP3A4 INHIBITORS (nitroimidazole antifungal
agents, diltiazem, verapamil, troleandomycin)
1.79
Erythromycin
1.48
Amoxicillin
5.35
Erythromycin CYP3A4 inhibitors
0.2
1
3
5
7
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Pharmacogenetics of acetaminophen
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.
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Challenges and measures in PGx development(Gurwit
z, Public Health Genomics 2009 12 134-41)
Public Health Genomics Pharmacogenetics in
Europe Barriers and Opportunities European
Commission Joint Research Center
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La farmacogenetica nella clinica geriatrica-
prospettive future-
Current Drug Metabolism 201112621-634 Pharmacog
enetics 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
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Davide Seripa (dseripa_at_operapadrepio.it) Laborato
rio di Gerontologia-Geriatria Sig.ra Carolina
Gravina Sig.ra Maria Urbano Dott.ssa Giulia
Paroni Dott.ssa Grazia DOnofrio 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