Inhibition of T-cell activation and proliferation by mycophenolic acid in patients awaiting liver transplantation: PK/PD relationships.
Mycophenolic acid (MPA) plasma concentrations were reported to be associated with a decrease in T-cell proliferation, and in both IL-2 α-chain (CD25) and transferin receptor (CD71) expression. The aim of this study was to confirm, quantify and model these PK/PD relationships. Full profiles of MPA plasma concentrations, T-cell proliferation, intracytoplasmic IL-2 and TNF-α expression, and both CD71 and CD25 expression were collected over the 12h after dosing in 10 patients on the waiting list for liver transplantation. Data were analyzed using NONMEM(®). Both CD25 and CD71 expression and T cell proliferation clearly decreased (median of decrease from baseline 62%, 68% and 94%, respectively) with increasing MPA concentrations, in contrast to IL-2 and TNF-α expression. The CD25 and CD71 baseline expression (E(0)) and maximum effect (E(max)) were correlated with the E(0) and E(max) values of T-cell proliferation (r(2)=0.509 and r(2)=0.622, respectively). The CD25, CD71 expression and T-cell proliferation profiles were adequately fitted using a sigmoid inhibitory E(max) model. Low estimated values (≤2 mg/L) for 50% inhibitory MPA concentrations were obtained. This study confirmed a transient MPA concentration-dependent decrease in T-cells expressing CD25 and CD71 and a strong reduction of T-cell proliferation and showed that CD25 and CD71 expression was correlated with T-cell proliferation.
INSERM, UMR-S850, Limoges, France. aurelie.premaud@unilim.fr
Aurélie
A
Prémaud
Annick
A
Rousseau
Gyasi
G
Johnson
Cindy
C
Canivet
Peggy
P
Gandia
Fabrice
F
Muscari
Jean Marie
JM
Peron
Lionel
L
Rostaing
Pierre
P
Marquet
Nassim
N
Kamar
D000328:Adult; D000368:Aged; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics* / Q000494:pharmacology*; D016031:Liver Transplantation / Q000276:immunology*; D008213:Lymphocyte Activation / Q000187:drug effects*; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology
D007166:Immunosuppressive Agents; D009173:Mycophenolic Acid