Mycophénolate mofétil

Transcription

1 Mycophénolate mofétil O OH CH 3 O O-desmethyl O glucosides OH CH 3 OCH 3 CH 3 CYP 3A UGT2B7 C O HO O HO AcMPAG (acyl-glucuronide) ACTIF TOXIQUE O O CH 3 OCH 3 Mycophenolate (MPA) OH COOH UGT enzymes COOH O UGT1A9 O HO O CH 3 HO OH O COOH OCH 3 MPAG (phenyl-glucuronide) INACTIF Cycle Entérohépatique COOH Picard N et al. Ther Drug Monit. 2004;26(6): Picard N et al. Drug Metab Dispos. 2005;33(1): CH 3 MRP2

2 Polymorphisme des gènes du métabolisme de MPA activité UGT2B7 A-1246G G749A T-1239C T815A G1073C G-840A C816T T1076C T-102C MRP2 C T 1 (32 exons: coding regions) 3 activité UGT1A9 Exon 1 Common UGT1A exons T- (UGT1A9) 275A C-2152T activité Proximal promoter region G8A T98C activité

3 Polymorphisme UGT et MMF 228/901 patients de l étude FDCC Gene SNP Allele Changement Wt Freq allèlique UGT1A8 518C>G *2 Ala173Gly G>A *3 Cys277Tyr UGT1A9-2152C>T Promoteur C>7 Promoteur T>C *3 Met33Thr C>T Intronique UGT2B7-842G>A Promoteur G>A Promoteur C>T *2 His268Tyr MRP2-24C>T Promoteur C>T Van Schaik RHN et al. Clin Pharmacol Therap, 2009;86(3):319.

4 UGT1A8 Van Schaik RHN et al. Clin Pharmacol Therap, 2009;86(3):319.

5 UGT1A9 Van Schaik RHN et al. Clin Pharmacol Therap, 2009;86(3):319.

6 Incidence de RAPB Incidence à un an : 15 % 95 % confidence interval OR Lower Higher p UGT1A9-275T>A or -2152C>T Nb Transplant Expresseur CYP3A HLA MM POUR UNE DOSE FIXE, LE GENOTYPAGE DE 36 PATIENTS Age POURRAIT EVITER UN EPISODE DE REJET AIGU C0 tacrolimus Female Induction Living donor PRA<10 % Van Schaik RHN et al. Clin Pharmacol Therap, 2009;86(3):319.

7 Génomique Prédiction de l efficacité Rôle du SNP intronique rs du gène de l IMPDH2 Winnicki W et al. The Pharmacogenomics Journal 2010;10:70.

8 Inhibiteurs de la calcineurine Cyclosporine / Tacrolimus Cytochrome P450 P-glycoprotéine

9 Tacrolimus Metabolism Vena porta Systemic circ. : 25% Intestinal lumen Intestinal lumen Liver CYP3A P-gp CYP3A P-gp feces : 15% Intestinal metabolism : 50% Hepatic first pass : 10% l Tacrolimus intestinal metabolism is responsible for 50 % degradation of the total oral dose. l Enzymes involved in tacrolimus elimination : Cytochromes 3A (3A4 et 3A5) P-glycoprotein

10 CYP3A5 genetic polymorphisms 5 3 *1B *1C *8 *4 *9 *2 *10 CYP3A5*3 A6986G *5 * * *1D l CYP3A5 genetic polymorphisms CYP3A5*3 : A-->G in intron 3 Alternative splicing Protein truncation Absence of enzymatic activity CYP3A5*3/*3 genotype carriers do not express the enzyme. Only CYP3A5*1 carriers express the enzyme. Kuehl P et al. Nature genetics 2001;27:383.

11 P-glycoprotein, the ABCB1 (MDR-1) gene product l Transmembrane ATP-dependent efflux pump l Export of xenobiotics including cyclosporine, tacrolimus, rapamycin l Expressed in various endothelial and epithelial cells l Affects the absorption, distribution, metabolism and excretion of its substrates. In the gut: strong expression and function of P-gp absorption alteration in expression and function of P-gp absorption l Genetic polymorphisms (Hoffmeyer S, PNAS 2000; 97 : ) Functional

12 Distribution histogram of tacrolimus daily doses one month after tacrolimus initiation Number of patients Ex 12: wt/wt Ex 21: wt/wt Ex 26: wt/wt Ex 12: m/m Ex 21: m/m Ex 26: m/m Tacrolimus daily dose (mg/kg/d) at 1 month Anglicheau D et al. J Am Soc Nephrol. 2003;14(7):

13 Daily doses and concentration/dose ratios of tacrolimus according to the genotypes derived from the 2 predominant haplotypes Haplotypes 1 and 2 are derived from the exon 12, 21 and 26 SNPs: haplotype 1: C-G-C; haplotype 2: T-T,A-T. ± 60% The three genotype groups were compared using the Kruskal-Wallis test ( a p 0.05) Anglicheau D et al. J Am Soc Nephrol. 2003;14(7):

14 Rationale : clinical data P<0.03, Kruskall Wallis Tacrolimus Daily Dose (mg/kg/d) ns 0.02 ns.05 *1/*1 (n = 4) *1/*3 (n = 9) *3/*3 (n = 67) Patients with the CYP3A5*1 allele (i.e. CYP3A5 expressors) require more tacrolimus to reach target predose concentrations compared with CYP3A5*3/*3 genotype (i.e. CYP3A5 non-expressors). Thervet E et al. Transplantation. 2003;76(8):

15 Clinical consequences of CYP3AP1 polymorphism: association with the time to rejection CYP3AP1*1/*3 or *1/*1 (CYP3A5 expressors) CYP3AP1*3/*3 (CYP3A5 non-expressors) In CYP3AP1*1 carriers (expressing CYP3A5 protein), the time to achieve target tacrolimus concentration was delayed, and the rejection occurred earlier. MacPhee et al. Am J Transplant 2004

16 Background : dose pre-transplant All patients 0.2 mg/kg/d CYP3A5 expressors : 0.30 mg/kg/d CYP3A5 non expressors : 0.15 mg/kg/d Haufroid et al. Am J Transplant 2006;6:2706

17 DESIGN Transplantation Genotyping Randomization Usual daily dose Daily dose according CYP3A5 Pharmacokinetic parameters Clinical data

18 Primary endpoint Proportion of patients within therapeutic range (10-15 ng/ml) p = 0.03

19 Analysis according to genotype 3A5 expressors *1/*1 (4 %) High metabolism 70 Control (5 %) : 5,6±2,35 Adapted (3 %) : 14±2,35 3A5 low epressors *1/*3 (17 %) Low metabolism Control (15 %): 10,1±1,59 Adapted (19 %) : 12,3±1,40 3A5 non expressors *3/*3 (79 %) Absence of metabolism Control (80 %) : 16,6±0,83 Adapted (78 %) : 12,0±0,86 40 p = 0,035 p = 0,26 p < 0, CYP*1/*1 CYP*1/*3 CYP*3/*3 Adapted Control

20 Secondary endpoints Number of dose modification Delay for targeted C0 p < Adapted 75 % Control 50 % 25 % P= Control Adapted D8 D

21 Clinical outcome Control Adapted Patient survival 100 % 97 % Graft survival 95 % 92 % BP acute rejection 7.1 % 8.9 % Renal function

22 Min SI et al. Transplantation 2010;90:1394. CYP3A5 et rejet

23 Tacrolimus nephrotoxicity Naesens M et al. JASN 2009 ; 20 : 2468.

24 Tacrolimus nephrotoxicity Naesens M et al. JASN 2009 ; 20 : 2468.

25 Tacrolimus nephrotoxicity Naesens M et al. JASN 2009 ; 20 : 2468.

26 CYP3A5 et Fibrose à un an Miura Y et al. Transplantation 2011;91:78.

27 CYP3A5 et évolution de la fibrose Miura Y et al. Transplantation 2011;91:78.

28 Cyclosporine Pharmacogenetics

29 Paramètres pharmacocinétiques Polymorphisme Génotype n C 0 /dose (µg/l)/(mg/kg) C max /dose (µg/l)/(mg/kg) AUC 0-4 /dose (h.mg/l)/(mg/kg) AUC 0-12 /dose (h.mg/l)/(mg/kg) Temps moyen d absorption (h) Demi-vie terminale (h) CYP3A5 *1/*3 *3/* ± ± ± ± ± ± 0.74 *1/* ± ± ± ± ± ± 0.22 *1/* ± ± ± ± ± ± 0.73 MDR-1 129T>C T/T ± ± ± ± ± ± 0.7 T/C ± ± ± ± ± ± 0.5 MDR C>T C/C ± ± 0.17 a 1.15 ± 0.40 b 2.15 ± ± ± 0.51 C/T ± ± 0.16 a 1.37 ± 0.43 b 2.48 ± ± ± 0.84 T/T ± ± 0.15 a 1.26 ± 0.30 b 2.19 ± ± ± 0.56 MDR G>(T, A) G/G ± ± ± ± ± ± 0.53 G/mutant ± ± ± ± ± ± 0.77 mutant/mutant ± ± ± ± ± ± 0.77 MDR C>T C/C ± ± ± ± ± ± 0.76 C/T ± ± ± ± ± ± 0.65 T/T ± ± ± ± ± ± 0.71

30 Rôle pour la survie? Kreutz R et al. Pharmacogenomics J Dec;8(6):