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 12 h 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 (E0) and maximum effect (Emax) were correlated with the E0 and Emax values of T-cell proliferation (r2 = 0.509 and r2 = 0.622, respectively). The CD25, CD71 expression and T-cell proliferation profiles were adequately fitted using a sigmoid inhibitory Emax 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.

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