Pharmacokinetics of Mycophenolic Acid and Its Glucuronide Metabolites in Stable Adult Liver Transplant Recipients With Renal Dysfunction on a Low-Dose Calcineurin Inhibitor Regimen and Mycophenolate Mofetil

Abstract

Low-dose calcineurin inhibitors (CNIs) in combination with a fixed dose (2 g/d) of mycophenolate mofetil (MMF) are a strategy to minimize exposure to cyclosporine (CSA) or tacrolimus (TAC) and thus reduce CNI-related side effects. This study compared the pharmacokinetics (PK) of mycophenolic acid (MPA) and its glucuronide metabolites in stable adult liver transplant recipients with moderately impaired renal function converted from a standard to a low-dose CNI regimen in combination with a fixed dose of MMF. Full 12-hour PK profiles of MPA, free MPA, the aryl glucuronide (MPAG), and the acyl glucuronide (AcMPAG) were obtained from 30 stable liver transplant patients on low-dose CNI (CSA, n = 12; TAC, n = 18) therapy at least 3 months after initiation of low-dose therapy. Predose CSA and TAC concentrations (quantified by liquid chromatography-tandem mass spectrometry) ranged from 17 to 35 and 1.1 to 3.7 microg/L, respectively. The PK variables for MPA, MPAG, AcMPAG, and free MPA displayed wide interindividual variability. Of note was the observation that there were no significant differences in the exposure to MPA, MPAG, and free MPA between the CSA and TAC groups. MPA area under the concentration-time curves (AUCs) ranged from 31.8 to 102.1 (median: 52.9) mg.h(-1).L(-1) in the CSA group and from 22.9 to 144.8 (median: 55.9) mg.h(-1).L(-1) in the TAC group. The AcMPAG AUC on patients under low-dose CSA therapy was higher than that observed under patients on low-dose TAC therapy, although this did not quite reach statistical significance (P = 0.057). Patients receiving CSA had a significantly higher AcMPAG Cmax but not AcMPAG AUC, suggesting that only peak CSA concentrations on a low-dose CSA regimen are sufficient to impair the biliary excretion of AcMPAG. In summary, the influence of CSA on the exposure to MPA was attenuated in stable adult liver transplant recipients on a low-dose CNI therapy in combination with a fixed dose of MMF as compared with patients on a standard CNI therapy. Dose adjustment according to drug concentration measurements is recommended to optimize dosing of MMF and to maintain adequate immunosuppression in patients converted to low-dose CNI therapy.

Cyclosporine alters correlation between free and total mycophenolic acid in kidney transplant recipients in the initial phase

“…did not observe any pharmacokinetic differences in free and, total MPA and MPAG. It was probably because of lower blood concentrations of cyclosporine in organ transplant recipients enrolled in their studies (23–25). Patel et al.…”

“…Beckebaum et al. reported that cyclosporine C 0 ranged from 17 to 35 ng/mL in liver transplant recipients (24). Ting et al.…”

“…Few reports are available on the free concentration of MPA in kidney transplant recipients other than the total concentration. No differences were reported in free MPA AUC 0-12 between CNI treatments in kidney, liver or heart transplant recipients (23)(24)(25). Only Grinyó et al reported lower AUC 0-12 of free and total MPA in kidney transplant recipients treated with cyclosporine than treated with tacrolimus (26).…”

“…Few reports are available on the free concentration of MPA in kidney transplant recipients other than the total concentration. No differences were reported in free MPA AUC 0–12 between CNI treatments in kidney, liver or heart transplant recipients (23–25). Only Grinyó et al.…”

Validation of an LC-MS/MS method to determine five immunosuppressants with deuterated internal standards including MPA

“…New therapeutic regimens combine immunosuppressants with different intracellular targets to lower blood concentrations and prevent undesired side effects [1-3]. This practice requires a precise and accurate analytical method, especially for the lower ranges of concentrations.…”