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.