brunet
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Curso práctico de trasplante de órganos sólidos11Congreso Societat Catalana de Trasplantament
Barcelona Marzo 2011
GENÉTICA Y TRASPLANTES
Farmacogenética e Inmunosupresión
Dra. M. Brunet
Farmacología . CDB. CIBERehd
Hospital Clínic. Universitat de Barcelona.
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The Pharmacogenetics Research Network: SNP Discovery to Clinical Drug Response - VOLUME 81 MARCH 2007
The home page of PharmGKB provides a straightforwardschema for understanding pharmacogenomics.
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Principales enzimas de biotransformación que pueden estar afectados por
polimorfismos genéticos que determinan su actividad enzimática
WE. Evans et al. Science 1999; 286: 487-491
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Polimorfismos genéticos de interés en inmunosupresión
Enzimas de biotransformación:
– CYP3A4 y CYP3A5 (TAC, CsA, SRL, EVL)
– UGT1A9 (MPA)
– TPMT ( Azatioprina ; FDA)
Proteínas reguladoras de transporte:
– MDR-1 or ABCB1 (nefrotoxicidad por CsA, TAC; Tx renal)
– MDR-1 (rechazo agudo; TAC,Tx hepático)
Polimorfismos de las dianas:
– IMPDH (MPA)
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The role of CYP3A4, CYP3A5 genetic polymorphisms in TAC absorption
CYP3A5*1 genotype carriers require more TAC to reach target trough concentrations.
Kidney: Anglicheau D et al, Am J Transplant 2005; Hesselink DA et al, Clin Pharmacol. Therapeutics 2003; Thervet E et al, transplantation 2003; Zhang X et al, Clin Transplant 2005;
Haufroid V et al, Pharmacogenetics 2004; V. Bach et al. ATC 2008
Liver: Goto M et al, Pharmacogenetics 2004; Masuda S et al, Pharmacol Therapy 2006; Yu S et al, Transplantation 2006 (CYP3A5*1 donor)
CYP3A5*1 more TAC vs. CYP3A5*3/*3
CYP3A4*1B more TAC vs. CYP3A4*1/*1
TAC Dose requirement
TAC
TAC
% eliminated TAC dose
% available TAC dose
Gut lumen
Gut wall
LiverCYP3A4P-gp
CYP3A4P-gp
Portal veinCYP3A5
CYP3A5
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Impact of Cytochrome P450 3A5 Genetic Polymorphism on Tacrolimus doses andConcentration-To_Dose Ratio in Renal Transplant Recipients.
E Thervet, D Anglicheau, B King et al, Transplantation 2003
The role of CYP3A5 genetic polymorphisms in TAC absorption
(wt) (wt)
Mean Cmin TAC :11.8 ± 2.8ng/mlNo difference Cmin TAC different genotypes
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* * **
**
** *
� Efecto del polimorfismo CYP3A5*1 en la farmacocinética de tacrolimus
1ªSemana
1r Mes 3r Mes
6º Mes 12º Mes
CYP3A5*1
Cm
inT
RL
/Dos
is
CYP3A5*1 CYP3A5*1
CYP3A5*1 CYP3A5*1
Cm
inT
RL
/Dos
is
Cm
inT
RL
/Dos
is
Cm
inT
RL
/Dos
is
Cm
inT
RL
/Dos
is
* * *
* *
V. Bach et al. ATC 2008 Pacientes trasplantados renales; n=123
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R e f e r e n c e S o li d O r g a n
T r a n s p la n t
E t h n ic B a c k g r o u n d
n C Y P 3 A 5 * 1 ( % )
* 1 /* 1 * 1 /* 3 * 3 /* 3 *
W e i- li n W e t a l L iv e r T r a n s p l a n t
2 0 0 6 ; 1 2 (5 ) :7 7 5
A d u l t L iv e r C h in e s e 5 0
1 3 5 0 3 7
S o n g f e n g Y e t a l . T r a n s p la n ta t io n
2 0 0 6 ; 8 1 :4 6
A d u l t L iv e r C h in e s e
1 0 0 1 1 .3 5 0 .9 3 7 .8
G o t o M e t a l P h a r m a c o g e n e t ic s
2 0 0 4 ; 1 4 (7 ) :4 7 1
A d u l t L iv e r J a p a n e s e 7 0 3 3 8 5 9
F u k u d o M e t a l. C l in P h a r m a c o l
T h e r 2 0 0 6 ; 8 0 :3 3 1
P e d ia tr ic l iv e r
J a p a n e s e 1 3 0 3 3 8 5 8
H e s s e lin k D A e t a l.
C l in P h a r m a c o l T h e r
2 0 0 3 ; 7 4 :2 4 5
A d u l t K id n e y
C a u c a s ia n 1 0 0 1 .6 1 7 .5 8 1
B a c h e t a l. P h a r m a c o g e n e t ic s
S u b m i t te d
A d u l t K id n e y
C a u c a s ia n 1 2 5 2 1 8 8 0
M o u r a d M e t a l. C li n C h e m L a b
M e d 2 0 0 6 ;4 4 ( 1 0 ) :1 1 9 2
A d u l t K id n e y
C a u c a s ia n 9 0 1 1 9 8 0
Incidence of CYP3A5*1 polymorphism
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Tacrolimus
Los portadores CYP3A5*1
� Requieren 2-3 veces la dosis convencional (presentanratios de concentración/dosis sig.inferiores).
� Sin impacto clínico en la incidencia de rechazo agudo(mayoria de estudios diversos tipos de Tx).
� Sin impacto clínico en la incidencia de nefrotoxicidad
Tx renal, hepático, cardíaco
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Hauser, J Am Soc Nephrol 2005;16:1501-11
ABCB1 (MDR1) genetic polymorphismsRelated to Cyclosporine (CNIs) Nephrotoxicity:
• Recipient: No consistent relationship with genetic polymorphisms in CYP3A4,CYP3A5 and ABCB1
• DONOR ABCB1 3435C>T seems to be correlated with nephrotoxicity
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Bernard O. & Guillemette C. Drug Metab Dispos. 2004;32:775-8.
Kuypers D.R.J. et al. Clin Pharmacol Ther. 2005;78(4):351-61.
Picard N. et al. Drug Metab Dispos. 2005; 33: 139-146.
Metabolismo del MPA: Polimorfismos genéticos que afectan la actividad metabólica o la expresión de los enzimas UGT
UGT1A9*3UGT1A9 T-275AUGT1A9 C-2152T
UGT2B7
� UGT1A9 alelo *3
Exón 33
Incidencia población caucásica 4.4%
� UGT1A9 C-2152T
Región promotora
Incidencia población caucásica 12.6%
� UGT1A9 T-275A
Región promotora
Incidencia población caucásica 16.8%
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Efecto de los polimorfismos UGT1A9 -275 T>A y -2152C>T en la exposición del MPA
6º Mes 12º Mes
No portador Portador
C-2152T / T-275A
No portador Portador
C-2152T / T-275A
Cm
inM
PA
/ D
osis
Cm
inM
PA
/ D
osis
1ª Semana 1r Mes 3r Mes
No portador Portador
C-2152T / T-275A
No portador Portador
C-2152T / T-275A
No portador Portador
C-2152T / T-275A
Cm
inM
PA
/ D
osis
Cm
inM
PA
/ D
osis
Cm
inM
PA
/ D
osis
* *
V. Bach et al. ATC 2008 D.R.J. Kuypers - Clin Pharm Ther 2005;78:351-361
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Single-nucleotide polymorphism
CYP3A5*1 CYP3A4*B UGT1A9*3 T-275A C-2152TT-275A and
C-2152T
Noncarriers 1 (<1%) 115 (93,5%) 120 (97,5%) 105 (85,4%) 107 (87%) NA
Total No. Of carriers 122 (99,1%) 8 (6,5%) 3 (2,4%) 18 (14,6%) 16 (13%) 14
Heterozygous carriers (1/2) 18 (14,6%) 7 (5,7%) 3 (2,4%) 18 (14,6%) 16 (13%) 14
Homozygous carriers (2/2) 104 (84,5%) 1 (<1%) 0 0 0 0
V. Bach et al. ATC 2008
Frequency of the T-275A and C-2152T SNPs
The obseved frequencies were consistent with the Hardy- Weinberg equilibrium
D.R.J. Kuypers - Clin Pharm Ther 2005;78:351-361.
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UGT1A9 -275T>A/-2152C>T Polymorphisms Correlate With Low MPA Exposure and Acute Rejection in MMF/Tacrolimus-Treated Kidney Transplant Patients.RHN van Schaik et al. Clin. Pharmacol. Therapeutics. 2009
� Method
338 adult renal transplant patients
163 Tacrolimus + MMF (1 or 2 gr/day; 93 FD) + prednisolone
� Carrying the UGT1A9 -275T>A and /or -2152C>T polymorphism significantly predicted acute rejection in fixed-dose (FD) MMF treated patients receiving TAC.
Odds ratio 13.3, 95% confidence interval; p< 0.05.
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Single nucleotide polymorphisms (SNPs)
Pharmacogenetics
Genetic polymorphismsMetabolizing enzymes
P-glycoproteinsMRP2
Genetic polymorphismsTarget
CytokinesReceptors
Adhesion moleculesGrowth factors
Numerous SNPs affecting drug target and drug immunomodulatory effect in organ transplant patientshave been associated with acute rejection or toxicity
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IMPDH1 Gene Polymorphisms and Association with Acute Rejection in
Renal Transplant Patients. J Wang et al. Clin. Pharmacol. Ther. 2007
Plasma concentrations of MPA are affected by a number of gene polymorphisms*
� 191 kidney Tx; TAC+MMF+ Pred.
� 456 kidney Tx; TAC +MMF; CsA+MMF
IMPDH1 Gene Polymorphism SNP rs2278293
Was associated with a lower risk ofBPAR and a higher risk ofleucopenia over the first yearpost-transplantation.
Genetic Polymorphisms & Drug Response & Clinical Outcome
Polymorphisms in type I and II inosine monophosphate dehydrogenasegenes and association with clinical outcome. O Gensburger et al.
Pharmacogenetics & Genomics 2010
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� IMPDH2 3757T>C carriers havehigher IMPDH activity.
Sombogaard et al. Pharmacogenetics& Genomics 2009
� IMPDH 2 Gene Polymorphism SNP 3757 CC + CT higher incidence ofBPAR (OR 3.4, p=0.006).
Caesar study Transplant Int. 2008
Genetic Polymorphisms & Drug Response & Clinical Outcome
IMPDH2 Gene Polymorphisms and Association with AcuteRejection in Renal Transplant Patients
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MMF (MPA)
� UGT1A9 -275/-2152 SNPs are associated with decreased MPA exposure.
� In fixed-dose MMF/TACRO co-treated kidney Tx patients correlate with acute rejection (OR 13 [1.1-162])
� IMPDH 2 Gene Polymorphism SNP 3757 CC + CT was associated withhigher incidence of BPAR (OR 3.4, p=0.006).
� IMPDH1 Gene Polymorphism SNP rs2278293 was associated with a lower risk of BPAR and a higher risk of leucopenia.
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Aplicabilidad clínica
Los análisis farmacogenéticos pueden identificar a pacientes con un mayor riesgo de ineficacia o efectos adversos.
MPA: IMPDH, UGT1A9 SNPs, relevantes en la practica clínica?
Análisis “universal” No justificado (FDA, EMEA)Si en situaciones de ineficacia o efectos adversos (IATDMCT)
1- Selección de la mejor dosis de inicioparalelamente monitorizar FC ?Considerar medicación concomitante?
2- En portadores de los SNPs UGT1A9 -275/-2152 Elejiríamos la mism dosis de MMFpara MMF/CsA o MMF/TAC?Elejiriamos CsA o TAC como medicación concomitante?
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Pharmacokinetics of
MMF, MPA & Metabolites
Intestine
Feces
Micofenolate mofetil
MPAGAc MPAG
Estearase
Micophenolic Acid
UDP-G transferaseββββ glucuronidasa Liver
Bilis
Blood
Urine (96%)
IntestinePlasma
PlasmaLiver
Enterohepatic
Circulation LiverWB
B. albumin 97%Tmax ≈≈≈≈ 30-50 min
2º Peak 6-12 h
Van Gelder T. et al. 2000
Kuypers D.R.J. et al. 2006CsA inhibits MRP2
CH3
OH
OCH3
O
OO
ON
O
MRP2
M. Brunet 2000
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MPA & CsAInteracciones Farmacocinéticas
MMF 2g + CsA
MMF 1g + TRL; MMF 2g + TRL
121425 17N =
MMF+CSAMMF+TRLMMF
Bas
al M
PA
(µ
g/m
L)
7
6
5
4
3
2
1
0
-1
1g/día
2g/día
**
121424 17N =
MMF+CSAMMF+TRLMMF
AU
C M
PA
(µ
g.h
/mL
)
100
80
60
40
20
0
1g/día
2g/día
**
T. Van Gelder et al. 2000; M. Brunet et al. 2003; DRJ. Kuypers et al. 2006; JM. Grinyó et al. (in press)
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Aplicabilidad clínicaLos análisis farmacogenéticos pueden identificar a pacientes con un mayor riesgo de ineficacia o efectos adversos.
TAC: CYP3A5, ABCB1, relevantes en la practica clínica?
Análisis “universal” No justificado (FDA, EMEA)Si en situaciones de ineficacia o efectos adversos (IATDMCT)
1- Selección de la mejor dosis de inicioPortadores CYP3A5*1 (*1/*1;*1/*3), 2-3veces la dosis conven.
Considerar medicación concomitante?Ketoconazol, Afecta a nuestra decisión referente al SNP?Considerar función hepática?pacientes VHC+, afecta nuestra decisión referente L SNP?
Aconsejable siempre Monitorizar FC TAC
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Curso práctico de trasplante de órganos sólidos11 Congreso Societat Catalana de Trasplantament
Barcelona Marzo 2011
Farmacogenética e Inmunosupresión
Gracias !