Plasma and intracellular pharmacokinetic-pharmacodynamic analysis of mycophenolic acid in de novo kidney transplant patients

Objectives: Little is known about the correlation between the inosine-monophosphate dehydrogenase (IMPDH) activity and mycophenolic acid (MPA) concentrations in peripheral-blood-mononuclear cells (PBMCs), where the drug is acting. The aim of this study was to analyze the relationship between plasma or PBMC MPA levels, as pharmacokinetic (PK) markers, and the intracellular IMPDH enzyme activity, as a pharmacodynamic (PD) biomarker, in kidney transplantation. Design and methods: Forty de novo renal transplant patients were enrolled in this prospective study. The sampling was performed on the day before transplantation and at T₀, T_1.5 and T_3.5 following the morning dose, on days 2, 4 and 10 post-transplantation. All subjects were treated with a fixed MMF dose (500mg twice-a-day). IMPDH activities were determined by HPLC, and MPA plasma or PBMC concentrations were obtained by LC-MSMS. Results: Important inter-patient variability was observed both for the PK and PD biomakers. Pre-dose IMPDH activity, surprisingly, increased during the 10days post-transplantation. As expected, a significant inverse relationship was found between IMPDH activities and MPA concentrations in both plasma and PBMCs. A significant correlation was found between plasma and PBMC MPA values. Maximum IMPDH inhibition was found mostly at T_1.5, before returning to its pre-dose levels at T_3.5. IMPDH inhibition at T_1.5 better correlated with plasma MPA AUC_0-3.5 (p=0.027) than with PBMC AUC_0-3.5 (p=0.323). Mean MPA plasma concentrations paralleled the enzyme inhibition profiles and decreased strongly at T_3.5, whereas the decreasing slope of MPA concentrations in PBMCs appeared slower. Conclusions: These findings suggest that PBMC MPA concentrations do not provide any better correlation with the IMPDH activity than plasma MPA values, most likely due to the correlation between plasma and PBMC MPA levels and to the important interpatient variability both in MPA levels and enzyme activities.