Alberto PilottoDepartment of Medical Sciences
Geriatric Unit & Gerontology-Geriatrics Research LaboratoriesCasa Sollievo della Sofferenza, IRCCS
San Giovanni Rotondo, Italy
Farmacogenetica delle rezioni avverse
Congresso Nazionale SIGGFirenze, 29 novembre 2007
ADR-InADR avvenute in
pazienti mentre erano ricoverati in ospedale
ADRADR--AdAdADR che hanno ADR che hanno indotto ricovero indotto ricovero
in ospedalein ospedale
10,9
4,7
0
5
10
15
ADR-In ADR-Ad
%
Lazarou, JAMA 1998; 279:1200-5
Incidenza di ADR in pazienti ospedalizzati: Incidenza di ADR in pazienti ospedalizzati: metameta--analisi di 39 studi prospettici negli USA, 1966analisi di 39 studi prospettici negli USA, 1966--19961996
62.480 pazienti: Prevalenza ADR severe=6.7%, ADR fatali=0.32%
≈ 6.7% ≈
23,5
20,6
13,7
12,7
3,9
3,9
2,9
2,9
1,9
1,9
0 5 10 15 20 25
NSAID/Aspirin
Warfarin
Low dose Aspirin
Digoxin
Amiodarone
Ace Inibhitors + diuretics
Analgesic drugs
Antibiotics
B blockers
Antidiabetic drugs
%
Farmaci responsabili di ADR severa
Franceschi, Drug Saf 2007, in press
1756 patients, admitted to Geriatric Unit (Nov. 2004-Dec.2005)
ADR = 102 cases (5.8%) of all admissions
PharmacogeneticsPolymorphisms in the genes that code for drug-metabolising enzymes, drug transporters, drug receptors can affect: - efficacy- interactions with other drugs- adverse drug reactions
Ginsburg, Arch Intern Med 2005; 165: 2331-6
It is likely to be among the first clinical applications of the Human Genome Project
Mutazioni genetiche
Rare, presenti < 1% della popolazione, recenti dal punto di vista evolutivo, modifiche fenotipiche rilevanti (malattie mendeliane)
Dallapiccola B et al, 2006
Comuni, presenti > 1% della popolazione,antiche dal punto di vista evolutivo, piccole variazioni fenotipiche, mediano con i fattori ambientali (fattori di rischio), polimorfismi
Guzey, Curr Top Med Chem 2004; 4:1411-21
2D619%
3A4/536%
2A63%
2B63%
2E14%
2C916%
2C198%
1A211%
Genotyping as a tool topredict ADRs
More than 80% of human drug
oxydation is due to six CYP isoenzymes:
3A4/52D62C192C9
Cytochrome P 450 Systemand drug metabolism
CYP 2 C 9
Home page of the Human Cytochrome P450 (CYP) Allele Nomenclature Committee (http://www:cypalleles.ki.se)
Nomenclatura del sistema del Citocromo P450
Superfamiglia genica(Citocromo P450)
Famiglia genica
Sottofamigliagenica
GeneAllele
Aplotipo
*1 A
Drugs that are substrates for CYP 3A4SUBSTRATI 3A4
Ca++ Antagonistidiltiazem, felodipina,nifedipina, verapamile
Benzodiazepinealprazolam, midazolam, triazolam
Statineatorvastatina, lovastatina
Antibiotici macrolidieritromicina,claritromicina
Agenti anti-HIVIndinavir, ritonavir, saquinavir
FORTI Agenti anti-HIVClaritromicinaKetoconazolo
MODERATIFluconazoloVerapamileSucco di pompelmo
LIEVIcimetidina
INIBITORI
FenobarbitalCarbamazepinaOxcarbamazepinaGlicorticoidiRifampicinaRifabutinaTroglitazone
INDUTTORI
http://medicine.iupui.edu/flockhart/table/htm 2007
Metabolism after Oral administration of Felodipineand its interaction with CYP3A4 Inhibitors
Wilkinson, NEJM 2005; 352: 2211-21
Oral dose 100%
100%
100% 30%
90%
CYP3A4
Grapefruitjuice
CYP3A4
45%15%
45%15%Felodipinebioavailability
0.2 1 3 5 7
RiskRisk of of suddensudden deathdeath fromfrom cardiaccardiac causescauses accordingaccording totouseuse of CYP3A4 of CYP3A4 inhibitorsinhibitors and and antibioticsantibiotics (1476 (1476 casescases))
Erythromycinalone
1.790.85 3.76
Amoxicillinalone
1.480.74 2.97
Erythromycin + CYP3A4 inhibitor
5.351.72 16.6
Ray, NEJM 2004; 351: 1089-96
CYP3A4 INHIBITORS: nitroimidazole antifungal agents, diltiazem, verapamil, troleandomycin
Beta-bloccanti:Carvedilolo, Metoprololo, propanololo, Timololo
Antidressivi:Fluoxetine, Fluvoxamine, ImipramineParoxetina
Antipsicotici:Aloperidolo, Risperidone
Oppioidi:Codeina, oxicodone
Antiaritmici: Flecainide, Mexiletina, Propafenone
Cacabelos, Curr Alzheimer Res 2007;4:479-500
Drugs that are substrates for CYP 2D6
7,19,0
32,2
51,6
0
EM IM PM UM
%
CYP 2D6
Metabolizers
Molecolar genetics of CYP 2D6: clinical relevanceCYP 2D6 genotype and plasma concentration of psychotropic drugs
RISPERIDONE
16,3
29,4
0
10
20
30
EM PM
%
HALOPERIDOL
Bertilsson, Br J Clin Pharmacol 2002; 53:111-22
p<0.01
Scordo, Psychopharmacology 1999; 147:300-5
CYP 2C19 polymorphisms and PPI: effects of on gastrin, PG I, and chromogranin A
72 patients on long-term treatment (>1 year) with omeprazole 20 mg daily
52,1
14,70
10
20
30
40
50
60
Gastrin
Wt/Wt Wt/M1 (Poor Metabolizers)
2,5
7,3
0
2
4
6
8
Chromoganin A
193
147
0
50
100
150
200
250
Pepsinogen I
Sagar, Aliment Pharmacol Ther 2000;14:1495-502
Clinical usefulness of serum Clinical usefulness of serum pepsinogenspepsinogens I and II, gastrinI and II, gastrin--1717and antiand anti--Helicobacter pylori antibodies in the management Helicobacter pylori antibodies in the management
of dyspeptic of dyspeptic patientspatients in in primaryprimary carecare
Germanà, Dig Liver Dis 2005;37:501–8
362 patients with dyspeptic symptomsF=208, M=154, mean age=50.6 ± 16 years, range=18-88 years
Normal (n=138) Non-atrophic chronic gastritis (n=89) Atrophic chronic gastritis (n=60)
98,4121,5
87,1
020406080
100120140160
PGI
ug/L
6,9 8,3
21
05
1015202530
Gastrina
pmol
/L
p<0.001 p<0.001
Healthy stomach
H.pylori acquisitionAutoimmune
Inheritedgene error
??
Chronic gastritis; non-atrophic
- cytokines, growth factors- cell proliferation
Chronic atrophicgastritis
Carcinoma diffuse type
Carcinoma Intestinal type
Dysplasia
Intestinal metaplasia
Sipponen, APT 1998,12 (Suppl 1):61-71
Lee, Pharmacogenetics 2002; 12:251-63
CelecoxibDiclofenacNaproxenNimesulidePiroxicam
TolbutamideGlipizide
Warfarin
Drugs that are substrates for CYP 2C9
10
35
7
0
10
20
30
40
Poor Intermediate Ultrarapid
%
Allele *1/*1Wild Type
CYP 2C9
Allele*2, *3
Rischio di emorragia gastroduodenale da FANS: ruolo Rischio di emorragia gastroduodenale da FANS: ruolo dei polimorfismi genetici del Citocromo P450 2C9dei polimorfismi genetici del Citocromo P450 2C9
Farmaci: celecoxib, diclofenac, nimesulide, naproxene, piroxicam < 30 giorniH pylori negativi, no gastroprotezione
Emorragici (N°26) Controlli (N° 52)
Reference
0
20
40
60
80
2C9*1*1 *1*2 *1*3
p=0.03
OR=4.2(1.11-16.2)
OR=15.8(3.3-74.8)
p=0.0001
Pilotto et al, Gastroenterology 2007; 133: 465-71
0
10
20
30
40
50
60
Alle
le F
requ
ency
2C9 *2 allele 2C9 *3 allele
OR=4.0(1.28-12.4)
OR=1.6(0.57-4.45)
p=nsp=0.0001
CYP *1/*1 wild type
0.2 1 2 3 4
Association between CYP2C9 genetic variantsand anticoagulation-related outcomes
AssociationAssociation betweenbetween CYP2C9 CYP2C9 geneticgenetic variantsvariantsand and anticoagulationanticoagulation--relatedrelated outcomesoutcomes
INR > 31.40
Severe bleeding2.39
Higashi, JAMA 2002; 287: 1690-8
INR > 3 (3 weeks) 1.82C9*2
2C9*32.2Lindh,Clin Pharm Ther 2005;78:540-50
Risk of bleeding2.57
Margaglione,Thromb Haemost 2000; 84: 775-8
2C9*2 or *3
2C9*2 or *3
Vitamin K Oxide Reductase Complex 1 (VKORC1) polymorhisms and warfarin dose
A = low-dosehaplotype group
B= high-dosehaplotype group
Rieder, NEJM 2005;352: 2285-93
Retrospective study in European-American patientsin long-term maintenance treatment with warfarin
6,24,7
2,7
0
5
10
A/A A/B B/B
%
Maintenance dose of warfarin (mg daily)
p<0.001
Serotonin Transporter Gene-Linked PolymorphicRegion (HTTLPR) and antidepressant ADRs
50%
40%
10%
0 0.2 0.4 0.6
S/S
S/L
L/L HTTLPR S/S homozygotes and
S/L heterozygotessuffered more of antidepressant-
associated ADRs(p=0.002)
Popp, Pharmacogenomics 2006; 7: 159-66
109 patients treated with:mirtazapine (65), citalopram (10), escitalopram (7), venlafaxine (6),
paroxetine (5), doxepin (5), other antidepressants (11)
Farmacogenetica Citocromo-P450 indipendente
Sulfamidici, isoniazide, idralazinaN-acetiltransferasi (NAT2)
IrinotecanUDP glucoronisiltransferasi(UGT1A1)
Azatioprina, 6-mercaptopurinaTiopurina metiltransferasi(TPMT)
5-fluorouracileDiidropirimidina deidrogenasi
(DPD)
MetotrexateMetilenetetraidrofolato reduttasi
(MTHFR)
Mladosievicova, Neoplasma 2007;54:181-8
Criteri di Evitabilità di ADR (Hallas)1756 patients, admitted to Geriatric Unit (Nov. 2004-Dec.2005)
ADR = 102 cases (5.8%) of all admissionsDefinitely avoidable Possible avoidable
17 (16.5%) 29 (28.4%) 32 (31.4%)Inappropriate prescription
No gastroprotection Inadequatemonitoring
NSAID/ASA 5 (29.4%) 29 (100%) 1 (3.1%)
Warfarin 3 (17.6%) - 13 (40.6%)
Digoxin 1 (5.9%) - 12 (37.5%)
Antidiabetics - - 2 (6.3%)
Amiodarone 1 (5.9%) - 1 (3.1%)
Antihypertensive 4 (23.5%) - 3 (9.4%)
Neurological 3 (17.6%) - -Franceschi, Drug Saf 2007, in press
88,5
14,3
9,6
0 20 40 60 80 100
Analgesiscs
Anti-hypertensive
Antidrepressants
%
Defining the opportunity for pharmacogeneticintervention in primary care
Grice, Pharmacogenomics 2006; 7: 61-5
607 patients in primary care (USA), 16 drugs cause ADRs
28.6% took > 1 ofpharmacogenetic
ADR-associated drugs
Risk factors:-Old age (p<0.001)
- Chronic disease (p<0.001)
Donato Antonacci, MDLeandro Cascavilla, MDMichele Corritore, MDPiero D’Ambrosio, MDMaria Grazia Longo, MDValeria Niro, MDFrancesco Paris, MDGiuseppe Rinaldi, MDCarlo Scarcelli, MDMargherita Zurro, MD
Marilisa Franceschi, MDFilomena Addante, MDGiuliana Placentino, Psicol.Grazia D’Onofrio, Psicol.Anna Maria Pazienza, Stat.
Davide Seripa, BDM.Giovanna Matera, BDVeronica Goffredo, BDCarolina Gravina, Tec. Lab.Maria Urbano, Tec. Lab.