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Farmacogenetica e farmacogenomica
nell’anziano
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
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
(Meyer, Nature Rev Genet 2004;5:669-676)
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.
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.
Pharmacogenomics: challenges and opportunities
(Roden, Ann Internal Med 2006;145:749-757)
Small effect
Pharmacogenomics
We are here!
Large effect
Pharmacogenetics
Single gene
Small number
of genes
Great number
of genes
Whole genome
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
Evidence for the evolution of CYP gene superfamily
by gene duplications
CYP3A3
CYP3A4
CYP3A5
CYP3A5P1
CYP3A5P2
Chromosome 7
CYP2C8
CYP2C9
CYP2C18
CYP2C19
Chromosome 10
CYP2D6
CYP2D7P
CYP2D8P
Chromosome 22
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.
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 (*)
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
Maggiori famiglie geniche del CYP
Famiglia CYP1:
CYP1A1; CYP1A2; CYP1B1
Famiglia CYP2:
Famiglia CYP3:
CYP2A6; CYP2A13; CYP2B6; CYP2C8; CYP2C9; CYP2C19; CYP2D6; CYP2E1;
CYP2F1; CYP2J2; CYP2R1; CYP2S1
CYP3A4; CYP3A5; CYP3A7; CYP3A43
Famiglia CYP4:
CYP4A11; CYP4A22; CYP4B1
(*) Human Cytochrome P450 (CYP) Allele Nomenclature Committee (http://www.imm.ki.se/CYPalleles/)
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.
2E1 2B6
2C19 4% 3%
8%
P2A6
3%
3A4/A5
36%
1A2
11%
2C8/9
16%
2D6
19%
Association between CYP2C9 genetic variants and
warfarin-related outcomes
1.40
CYP2C9*2 (R144C)
(Higashi, JAMA 2002)
2.39
CYP2C9*3 (I359L)
(Higashi, JAMA 2002)
1.8
CYP2C9*2 (R144C)
(Lindh, Clin Pharm Ther 2005)
2.2
CYP2C9*3 (I359L)
Severe
bleeding
(Lindh, Clin Pharm Ther 2005)
2.57
CYP2C9*2 or *3 (R144C or I359L)
Risk of
bleeding
(Margaglione, Thromb Haemost 2000)
CYP2C9 *1/*1 wild type
0
1
2
3
4
No
bleeding
Vitamin K Oxide Reductase Complex 1 (VKORC1)
polymorphisms and warfarin dose
(Rieder, NEJM 2005;352: 2285-93)
Maintenance dose of warfarin (mg/daily)
70%
0,62
60%
0,47
50%
40%
30%
0,27
20%
10%
0%
A/A
A/B
A = low-dose haplotype group
B = high-dose haplotype group
B/B
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
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
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
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
Platelet aggregation
CV events and/or death
p=0.02; HR=2.42,95%CI 1.18-4.99
p=0.02
50%
25%
40%
20%
30%
15%
20%
10%
10%
5%
0%
2C19*1/*1 2C19*1/*2 2C19*2/*2
(Ref.)
0%
2C19*1 (Ref.)
2C19*2
Reduced-function CYP2C19 genotype and risk of
adverse outcomes in patients treated with clopidogrel
(Mega, JAMA 2010;304:1821-1830)
Meta-analysis of 9 studies evaluating 9685 patients
(91.3% with PIC and 54.5% with acute coronary syndrome)
1.55
CYP2C19*1/*2
Risk of CV,
MI or
stroke
1.76
CYP2C19*2/*2
2.67
CYP2C19*1/*2
Risk of
stent
thrombosis
3.97
CYP2C19*2/*2
0.2
1
2
3
4
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”
I FANS e l’emorragia gastroduodenale
Reclutati
(n = 78)
Bleeding
(n = 26)
No bleeding
(n = 52)
Allele
SNP-ID
DNA change
Protein change
Enzyme activity
CYP2C9*2
rs1799853
C430T
Arg144Cys
Decreased
CYP2C9*3
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.
I FANS e l’emorragia gastroduodenale
p = 0.034
OR = 4.2 (1.1 - 16.2)
Reference
p < 0.001
OR = 15.8 (1.1 - 16.2)
Il donepezil nel trattamento dell’Alzheimer
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.
• Mantenimento o miglioramento dello stato cognitivo
(valutato tramite ADAS-Cog e MMSE)
• Miglioramento dello stato funzionale (valutato tramite
ADL o IADL)
Le fenocopie
Fenocopia
Un fenotipo che somiglia ad un fenotipo genetico ma che ha cause ambientali.
Inibitori del CYP2D6
Fenocopia
(rispetto EM)
Induttori
del CYP2D6
Fenocopia
(rispetto EM)
Forti
Moderati
Deboli
Bupropion
Duloxetine
Amiodarone
PM
Dexamethasone
UM
Fluoxetine
Sertraline
Cimetidine
PM
Rifampin
UM
Paroxetine
Terbinafine
Quinideine
PM
PM
http://medicine.iupui.edu/clinpharm/ddis/table.asp
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)
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
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%.
Pharmacogenomic protocols in CNS disorders and dementia
(Cacabelos, Neurodegenerative Dis 2010;7:167-169)
About 25% of the 100 most prescribed drugs in USA and western
countries are psychotropic drugs currently used in dementia.
A trigenic cluster integrating CYP2D6+CYP2C19+CYP2C9 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
Pharmacogenetics of risperidone and haloperidol
CYP2D6 genotype and plasma concentration of psychotropic drugs
RISPERIDONE
(Scordo, Psychopharmacology 1999;147:300-305)
HALOPERIDOL
(Bertilsson, Br J Clin Pharmacol 2002;53:111-122)
p<0.01
30
20
29,4
16,3
%
10
0
EM
PM
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
Antidrepressants
9,60%
Anti-hypertensive
14,30%
Analgesics
88,50%
0%
20%
40%
60%
80%
100%
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)
Farmacogenetica dell’analgesia post-operatoria
Dolore post-operatorio
- protocolli terapeutici -
L1
Lieve
40 pazienti consecutivi in
terapia antidolorifica post-operatoria
L2
M1
Moderato
M2
Grave
G
Artrosilene
Zantac
Contramal
Plasil
Fentanest
Morfina
Protocollo terapeutico
L1
L2
M1
M2
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
- A volte
-
G
X
X
X
X
X
Farmacogenetica dell’analgesia 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.
http://www.drugbank.ca/
Farmacogenetica dell’analgesia post-operatoria
- risposta terapeutica e fenotipo metabolico Medie stimate
5
4.5
4
Punteggio VAS
3.5
3
EM
2.5
IM
2
PM
1.5
1
0.5
0
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
Tempo (ore)
EM versus IM: p = 0.015 – EM versus PM: p = 0.024 – IM vs PM: p < 0.001
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.
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)
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
Pharmacogenetics of acetaminophen
I
1
2
?
II
1
?
2
?
CYP2D6*1/*XN
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.
Public Health Genomics
Pharmacogenetics in Europe: Barriers and Opportunities
European Commission Joint Research Center
Challenges and measures in PGx development
(Gurwitz, Public Health Genomics 2009; 12: 134-41)
La farmacogenetica nella clinica geriatrica
- prospettive futureCurrent 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, organspecific 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
Davide Seripa
([email protected])
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