Renal graft function and low-dose cyclosporine affect mycophenolic acid pharmacokinetics in kidney transplantation

In kidney transplantation, the pharmacokinetics of mycophenolic acid (MPA), the active compound of mycophenolate mofetil (MMF), is influenced by concomitant immunosuppressive therapy, including cyclosporine (CsA). However, whether in the setting of immunosuppressive therapy minimization CsA still affects MPA pharmacokinetics, particularly in relation to varying degree of renal graft function deterioration, remains ill defined.

One hundred thirty-five complete MPA profiles were sequentially collected from 56 kidney transplant recipients given MMF and low-dose CsA as part of their immunosuppressive therapy. MPA pharmacokinetic parameters were correlated with blood CsA area under the curve (AUC0-12) and graft function as measured glomerular filtration rate (GFR). The relative contribution of CsA exposure and GFR to MPA kinetics in relation to other clinical parameters was determined by multivariate analysis.

Dose-adjusted MPA AUC0-12 negatively correlated with CsA AUC0-12. MPA exposure significantly increased when CsA AUC0-12 was below 2000 ng hr/mL. Stratification of MPA profiles according to stages of renal dysfunction showed that dose-adjusted MPA AUC0-12 was higher (P<0.001) in patients with severe (stage 4: 70.37±27.93 μg hr/mL/g MMF) than in those with mild (stage 2: 47.46±11.66 μg hr/mL/g MMF) or moderate (stage 3; 47.48±15.22 μg hr/mL/g MMF) renal insufficiency. At multivariate analysis GFR, serum albumin and hemoglobin levels, use of gastroprotective medications, and time posttransplant were identified as independent determinants of MPA AUC0-12.

In stable renal transplant recipients given MMF, tapering CsA dose and deterioration of renal graft function contribute to increased MPA exposure. Thus, monitoring plasma MPA pharmacokinetics should be advised, especially in patients on minimized CsA therapy with severe renal insufficiency.