Dúvidas
[email protected]
Arquivo
Farmacogenômica
Site
www.gilbertodenucci.com
Aulas - Unicastelo – Fernandópolis – 2014
Pacientes com o mesmo diagnóstico
Resposta
preditiva boa
para o
medicamento
Resposta preditiva
ruim ou ausente
Use outro
medicamento
Risco de toxicidade
alto
Diminuir a dose ou
usar outro
medicamento
Tratamentos estabelecidos com alta eficácia e % dos
pacientes beneficiados e não beneficiados com o
tratamento
Ensaio
Droga
Eventos (%)
Placebo
Tratad
Benefício/100 Ausência de
Benefício/100
Hope
Ramipril
17.8
14
3.8
96.2
APTC
Aspirina
14
10
4
96
FTT
Trombolíticos
11.5
9.6
1.9
98.1
4S
Simvastatina
28
19
9
91
EPIC
Abciximab
12.8
8.3
4.5
95.5
CURE
Clopidogrel
11.5
9.3
2.2
97.8
Farmacogenética
Alvos do
medicamento
Transportadores
Farmacodinâmica
Enzimas
metabolisadoras
Farmacocinética
Variabilidade na
eficácia ou toxicidade
Farmagenômica
Distribuição
Absorção
Excreção
Farmacogenômica
Afinidade do receptor
pela droga
Droga atuando em produtos gênicos
Curr Probl Cardiol, May 2003
The concept of pharmacogenetics.
Pharmacogenomics: Challenges and Opportunities - © 2006 American College of Physicians - Ann Intern Med. 2006;145:749-757.
Diastolic blood pressure response to metoprolol in hypertensive patients is
predicted by ADRB1 diplotype.
The Pharmacogenetics Research Network: From SNP Discovery to Clinical Drug Response - VOLUME 81 NUMBER 3 - MARCH 2007
Alelos da apo e
• apo e2
• apo e3
• apo e4
Kaplan-Meier em pctes com e
sem o alelo apoe4
~Proporção Vivo
1.00
Sem e4
N=312
0.95
0.90
e4-Portadores
N=166
0.85
0.80
0
500
1000
1500
2000
2500
Dias após Randomização
Tratamento com Placebo
Curr Probl Cardiol, May 2003
Tratamento com simvastatina reduz
mortalidade em
• 13% em pacientes não apo e4
• 50% em pacientes apo e4
Kaplan-Meier em pctes com e
sem o alelo apoe4
Proporção Vivo
1.00
Sem e4
N=301
e4-Portadores
N=187
0.95
0.90
0.85
0.80
0
500
1000
1500
2000
2500
Dias após randomização
Tratamento com Simvastatina
Curr Probl Cardiol, May 2003
Tiopurina Metiltransferase
•
•
•
•
•
•
Polimorfismo TPMT
Metila mercaptopurina – reduz F
Leucemia linfocítica aguda
10% intermediária – maior toxicidade
0.3% não tem TMPT – fatal
Genotipagem essencial
UDP-glucoronosiltransferase 1A1
•
•
•
•
Irinotecan – câncer de cólon, pulmão
Forma ativa inativada por glucoronidação
Aumento de 4x a toxicidade
Genotipagem alelo UGT1a1*28
Gene da colinesterase plasmática
•
•
•
•
•
Apnéia prolongada após succinilcolina
1 em 187 em Valencia
1 em 3460 europeus
1 em 25 x 106 asiáticos
Complicação facilmente tratada, não
há necessidade de genotipagem
Leucemia mielóide crônica
•
•
•
•
•
Translocação no cromossoma Filadelfia
Alterou localização dos genes bcr e abl
bcr-abl tirosina quinase fica ativa
Imatinib bloqueia especificamente
Imatinib 88% resposta positiva em pctes
Câncer de mama
• Herceptin – ab citotóxico contra Her-2/neu.
• Her-2/neu aumentada em 25% pctes
• Herceptina funciona somente nestes pacientes
Substratos para citocromo P4502D6
• b-bloqueadores – alprenolol, carvedilol, propranolol
• Anti-arrítmicos – flecainida, mexiletina, propafenona
• Neurolépticos – haloperidol, clozapina, olanzapina, risperidona
• Antidepresssivos – amitriptilina, clomipramina, paroxetina
• Antieméticos – ondansetrona, tropisetrona
• Outros – anfetamina, codeína, debrisoquina, dextrometorfano
Inibidores do citocromo P4502D6
• Neurolépticos – clomipramina, levopromazina, haloperidol
• Antidepressivos – fluoxetina, paroxetina, sertralina
• Antieméticos - metoclopramida
• Anti-histamínicos – clorfeniramina, cimetidina, clemastina,
difenilhidramina
• Outros – ritonavir, quinidina, amiodarona
Genótipo do citocromo P4502D6
• Metabolizadores ultrarápidos
• Metabolizadores rápidos
• Metabolizadores lentos
Genótipo do citocromo P4502D6
• Metabolizadores ultrarápidos – muito baixa em orientais
(<<1%), baixa em europeus do norte (<1%), 7% em
espanhóis, 29% em etíopes
• Metabolizadores rápidos
• Metabolizadores lentos – muito baixa em orientais
Tratamento de náusea e vômito in
quimioterapia - Tropisetron
• 42 pacientes, 30% tiveram náusea e vômito
• CitP4502D6 – maior frequência dos demais pacientes
• Genotipagem recomendável – evitaria emese severa em
1/50 pacientes.
A superfamília do citocromo P450
Isoenzima
Substrato típico
Comentários
CYP1A
CYP2A
Teofilina
Testosterona
Induzida por tabagismo
Induzida por tabagismo
CYP2B
CYP2C
Numerosos
Numerosos
Induzido por fenobarbital
Apresenta polimorfismo genético
CYP2D
Debrisoquina
Apresenta polimorfismo genético
CYP2E
CYP3A
Induzida por álcool
Nitrosaminas
Nifedipina/ciclosporina Induzida por carbamazepina
CYP4
Ácidos graxos
Induzida por clofibrato
Diferenças Farmacogenéticas das Enzimas
que metabolizam medicamentos
Enzima
Pseudocolinesterase plasmática
Desidrogenase alcoólica
CYP2C19
CYP2D6
CYP2C?
Acetil-N-transferase
Metiltransferase
a
Para caucasianos
Incidência de deficiência
ou metabolizadores lentosa
1 in 3000
Substratos típicos
Suxametônio (succinilcolina)
5-10% (approx. 90% em Asiáticos) Etanol
5% (approx. 20% em Asiáticos)
S-Mefenitoína, omeprazole
5 - 10%
Debrisoquina, espartina,
metoprolol, dextrometorfan
Fenitoína
Muito raro
Isoniazida, hidralazina,
Approx. 60% (approx. 5% em
procainamida
japoneses)
6-Mercaptopurina
0.5 %
Cytochrome P-450
Ribbon model
of CYP2C9
isozyme
CYP3A
50%
CYPD6
25%
5%
5%
CYP2C9
15%
Other
CYP1A2
Netter’s Iluustrated Pharmacology – Chapter 1 – Fig. 1.30
BIOSSÍNTESE DO TXA2
Estímulo
Fosfolipídeos
Fosfolipase A2
Ácido araquidônico
PGG2, PGH2
TX sintase
TXA2
Major pathways leading to the formation of thienopyridine active
metabolites
P2Y12 inhibitors: differences in properties and mechanisms of action and potential consequences for clinical use. European Heart Journal (2009) 30, 1964–1977
Fármacos antiplaquetários
 Derivados da tienopiridina
Ticlopidina
 Ticlopidina
• inibição irreversível do receptor de P2Y12 de ADP
• pró-droga – requer conversão a tiol por enzima do
citocromo P450 hepático
• rapidamente absorvida
• T1/2 curta com longa duração de ação
• início de ação lento (3-7 dias)
Clopidogrel
Major pathways leading to the formation of thienopyridine active
metabolites
Review: Acetyl-coenzyme A carboxylase: crucial metabolic enzyme and attractive target for drug discovery. CMLS, Cell. Mol. Life Sci. 62 (2005) 1784–1803.
Fármacos antiplaquetários
 Clopidogrel
- estreitamente relacionado com a ticlopidina
- vantagem em relação à ticlopidina – maior tolerabilidade
gastro-intestinal e menor risco de neutropenia e
trombocitopenia
- reduz taxa de AVC, IM
- reduz morte de pacientes com AVC ou IM recentes
- uso indicado após angioplastia (conjuntamente com o
ácido acetilsalicílico)
Variability in platelet aggregation between individuals in response to
clopidogrel
Review: Platelet Function Testing and Implications for Clinical Practice. J Cardiovasc Pharmacol Ther 2009; 14; 157.
Impact of clopidogrel loading dose on level of response measured by
inhibition of adenosine diphosphate (ADP)-induced platelet aggregation
Review: Platelet Function Testing and Implications for Clinical Practice. J Cardiovasc Pharmacol Ther 2009; 14; 157.
The ACAPULCO Study. Response to clopidogrel and prasugrel using 3
different definitions of response
Review: Platelet Function Testing and Implications for Clinical Practice. J Cardiovasc Pharmacol Ther 2009; 14; 157.
Significantly attenuated platelet inhibition by clopidogrel in carriers of the
CYP2C19² allele as compared with the wild-type homozygote CYP2C19¹
Review: Platelet Function Testing and Implications for Clinical Practice. J Cardiovasc Pharmacol Ther 2009; 14; 157.
INIBIDORES DE CITOCROMO P450
1A2
2B6
2C8
2C19
2C9
2D6
2E1
3A4,5,7
Cimetidina
Fluoroquinolonas
Fluvoxamina
Ticlopidina
Ticlopidina
Gemfibrozila
Montelukast
Fluoxetina
Fluvoxamina
Amiodarona
Fluconazol
Isoniazida
Amiodarona
Disulfiram
Inbidores de
Protease:
Indinavir
Nelfinavir
Ritonavir
Cetoconazol
Lansoprazol
Omeprazol
Ticlopidina
Bupropriona
Clorfeniramina
Cimetidina
Clomipramina
Fluoxetina
Haloperidol
Metadona
Paroxetina
Quinidina
Ritonavir
Amiodarone
Cimetidina
Claritromicina
Diltiazem
Eritromicina
Fluvoxamina
Itraconazol
Cetoconazol
Verapamil
*Risk of Rehospitalization for Patients Using Clopidogrel With
a Proton Pump Inhibitor*
Karen M. Stockl, PharmD; Lisa Le, MS; Armen Zakharyan, PhD; Ann S. M.
Harada, PhD, MPH; Brian K. Solow, MD; Joseph E. Addiego, MD; Scott
Ramsey, MD, PhD
/Arch Intern Med./ 2010;170(8):704-710.
•Background *
Recent pharmacodynamic and retrospective clinical analyses have
suggested that proton pump inhibitors (PPIs) may modify the
antiplatelet effects of clopidogrel bisulfate.
* Methods *
We conducted a retrospective cohort study of persons enrolled in a
multistate health insurance plan with commercial and Medicare clients to
evaluate adverse clinical outcomes in patients using clopidogrel plus a
PPI compared with clopidogrel alone. Patients who were discharged from
the hospital after myocardial infarction (MI) or coronary stent placement
and treated with clopidogrel plus a PPI (n = 1033) were matched 1:1
(using propensity scoring) with patients with similar cardiovascular risk
factors treated with clopidogrel alone.
Rehospitalizations for MI or coronary stent placement were evaluated for
up to 360 days. A subanalysis was conducted to study the impact of
pantoprazole sodium, the most used PPI.
* Results *
Patients who received clopidogrel
plus a PPI had a 93%
higher risk of rehospitalization for MI (adjusted
hazard ratio, 1.93; 95% confidence interval, 1.05-3.54; /P/ = .03)
and a 64% higher risk of rehospitalization for
MI or coronary stent placement (1.64; 1.16-2.32; /P/
= .005) than did patients receiving clopidogrel alone. Increased
risk of rehospitalization for MI or coronary stent placement was
also observed for the subgroup of patients receiving clopidogrel
plus pantoprazole (adjusted hazard ratio, 1.91; 95% confidence
interval, 1.19-3.06; /P/ = .008).
* Conclusions *
Patients who received clopidogrel plus a PPI had a significantly
higher risk of rehospitalization for MI or coronary stent
placement than did patients receiving clopidogrel alone.
Prospective clinical trials and laboratory analyses of biochemical
interactions are warranted to further evaluate the potential impact
of PPIs on the efficacy of clopidogrel.
Limitations and challenges associated with vitamin K antagonists. INR
international normalized ratio
Novel anticoagulants and the future of anticoagulation. Thrombosis Research (2009) 123 Suppl. 4, S50–S55.
After oral absorption, warfarin is transported to the liver where
CYP1A1, CYP1A2, and CYP3A4 metabolize the R-enantiomer and
CYP2C9 metabolizes the more potent S-enantiomer.
Pharmacogenetics of warfarin: regulatory, scientific, and clinical Issues - J Thromb Thrombolysis (2008) 25:45–51 – fig 01
Vitamin K is responsible for the carboxylation or activation of clotting factors II, VII, IX,
and X in the liver. Vitamin K reductase enzymes keep the vitamin in an active (reduced) state
Each box contains the median weekly warfarin dose for the different 1173C/T genotype, and the bars represent the interquartile
range. There was only one African American with the TT genotype.
Warfarin Response and Vitamin K Epoxide Reductase Complex 1 in African Americans and Caucasians
VOLUME 81 NUMBER 5 | MAY 2007 | www.nature.com/cpt
Maintenance dose of warfarin by VKORC1 1173C/T polymorphism, stratified by race.
Cytochrome P450 2C9 SNPs that are known to affect warfarin
metabolism
Pharmacogenetics of warfarin: regulatory, scientific, and clinical Issues - J Thromb Thrombolysis (2008) 25:45–51 – tab. 01
Cytochrome and Warfarin
Antithrombotic management of patients with prosthetic heart valves: current evidence and future trends. Lancet 2009; 374: 565–76.
Effect of VKORC1 haplotype on warfarin dose stratified by VKORC1 haplotype and
CYP2C9 status: either wild type (WT) or CYP2C9*2 and/or CYP2C9*3 mutants (MUT)
Primary cohort: UW (N = 185); Replication cohort: Wash U (N = 368)
Pharmacogenetics of warfarin: regulatory, scientific, and clinical Issues - J Thromb Thrombolysis (2008) 25:45–51 – fig 02
Challenges in Pharmacogenomics
Pharmacogenomics: Challenges and Opportunities - © 2006 American College of Physicians - Ann Intern Med. 2006;145:749-757.
Examples of Associations between Drug Response and Genetic Variants*
Pharmacogenomics: Challenges and Opportunities - © 2006 American College of Physicians - Ann Intern Med. 2006;145:749-757.
Definitions of commonly used terms
Pharmacogenomics: Bridging the gap between science and practice - J Am Pharm Assoc. 2010;50:e1–e17
Systematic approach to understanding polymorphisms
Pharmacogenomics: Bridging the gap between science and practice - J Am Pharm Assoc. 2010;50:e1–e17
HLA: a pharmacogenomics success story - Pharmacogenomics (2010) 11(3), 277–281
Pharmacogenomic risk factors for
adverse drug reactions
MEDICAMENTOS QUE SÃO METABOLIZADOS POR ISOFORMAS DO CITOCROMO P450
1A2
2B6
Clozapina
Bupropiona
Ciclobenzaprina
Ciclofosfamida
Efavirez
Metadona
Imipramina
Naproxeno
Teofilina
2C8
2C19
2C9
Inibidores de
Bomba de
Próton:
Omeprazole
Lansoprazole
Pantoprazole
Rabeprazole
AINEs:
Diclofenaco
Ibuprofeno
Piroxicam
Ciclofosfamida
Progesterona
Betabloqueadores:
S-metoprolol
Timolol
Antidepressivos:
Hipoglicemiantes orais:
Tolbutamida
Glipizida
Anti-epilépticos:
Diazepam
Fenitoína
Fenobarbital
Amitriptilina
Clomipramina
2D6
Antagonistas de Angiotensina II:
Irbesartan
Losartan
Amitriptilina
Clomipramina
Desipramina
Imipramina
Paroxetina
2E1
Paracetamol
Etanol
3A4,5,7
Antibióticos macrolídeos:
Claritromicina, eritromicina,
Anti-arrítmico:
Quinidina
Benzodiazepínicos:
alprazolam, diazepam, midazolam,
triazolam
Imunomoduladores:
Ciclosporina, Tacrolimus
Antipsicóticos:
Celecoxib
Fluvastatina
Naproxeno
Fenitoína
Sulfametoxazole
Tamoxifeno
Tolbutamida
Warfarina
Haloperidol
Risperidona
Codeína
Dextrometorfano
Flecainida
Ondansetrona
Tamoxifeno
Tramadol
Venlafaxina
HIV inibidores de protease:
indinavir, ritonavir, saquinavir
Anti-histamínicos:
astemizole, clorfeniramina
Bloqueadores de canais de cãlcio:
amlodipina, diltiazem, felodipina,
nifedipina, nisoldipina, nitrendipina,
verapamil
Estatinas:
atorvastatina, cerivastatina,
lovastatina
Bisórpma
Gleevec,
Haloperidol
Metadona,
Quinina
Sildenafil
Tamoxifeno
Vincristina