Mycophenolate Mofetil for Solid Organ Transplantation: Does the Evidence Support the Need for Clinical Pharmacokinetic Monitoring?

Abstract

The need for clinical pharmacokinetic monitoring (CPM) of the immunosuppressant mycophenolate mofetil (MMF) has been debated. Using a previously developed algorithm, the authors reviewed the evidence to support or refute the utility of CPM of MMF. First, MMF has proven efficacy for prevention of organ rejection in renal and cardiac transplant populations. In addition, the pharmacologically active form of MMF, mycophenolic acid (MPA), can be measured readily in plasma, and relationships between the incidence of rejection and MPA predose concentrations and MPA area under the curve (AUC) have been reported. A lower limit of the therapeutic range (MPA predose concentrations >1.55 microg/mL, as measured by enzyme multiplied immunoassay technique [EMIT], or MPA AUC >30 or 40 microg. h/mL, as measured by high-performance liquid chromatography [HPLC]) has been suggested to prevent rejection in renal allograft patients. Similarly, in cardiac transplant patients, decreased incidences of organ rejection have been reported in patients with MPA concentrations >2 or 3 microg/mL (using EMIT) and total AUC values >42.8 microg. h/mL (using HPLC). However, the relationship between pharmacokinetic parameters and adverse events in renal and cardiac transplant patients remains unclear. Due to the nature of antirejection therapy, the pharmacologic response of MMF is not readily assessable, and therapy is life-long. MPA pharmacokinetics exhibit large inter- and intrapatient variability and may be altered in specific patient populations due to changes in protein binding, concomitant disease states, or interactions with concurrent immunosuppressants. Therefore, on the basis of current evidence, CPM can provide more information regarding efficacy of MMF than clinical judgment alone in select patient populations. However, further randomized, prospective trials are required to clarify unresolved issues. Specifically, an upper limit of the therapeutic range, above which the risk of side effects is increased, needs to be elucidated for MMF therapy. Other future directions for research include determining a practical limited sampling strategy for MPA AUC; clarifying the relationship between free MPA concentrations, efficacy, and toxicity; and defining the pharmacodynamic relationship between activity of inosine monophosphate dehydrogenase (the enzyme inhibited by MPA) and risk of rejection or adverse effects.

Early Adequate Mycophenolic Acid Exposure is Associated with Less Rejection in Kidney Transplantation

“…The target C2 level in the first 2 months is 1700-2100 ng/mL. A 12-h MPA AUC (AUC [0][1][2][3][4][5][6][7][8][9][10][11][12] …”

“…Mycophenolate mofetil (MMF) has become standard therapy with microemulsion cyclosporine (Neoral) or tacrolimus. Several studies have found associations of mycophenolic acid (MPA, the active metabolite) exposure with both efficacy and toxicity (5)(6)(7)(8)(9). After an analysis of the studies, a consensus group has proposed a therapeutic window for MPA (30-60 mg * h/L) (8).…”

Mycophenolic Acid Pharmacokinetics Early After Kidney Transplant

“…9,10 Furthermore, early after transplant, high variations between patients in AUC has been documented. 11,12 Therefore, therapeutic drug monitoring of MMF is recommended early after transplant. 13 The main purpose of this study was to determine the MPA pharmacokinetic profile early after transplant in Iranian kidney graft recipients.…”

Therapeutic monitoring of mycophenolic acid in liver transplant patients

“…Several publications have recommended individualization of MMF therapy based on plasma concentration measurements because of (1) large variability in the pharmacokinetics of mycophenolic acid (MPA), the active metabolite of MMF in patients; (2) time-dependent changes in the pharmacokinetics of MPA within patients; (3) lack of a correlation between dose and plasma MPA concentrations; (4) variability in the MPA concentration / pharmacokinetics based on coadministered immunosuppressive drugs; (5) a decrease in the incidence of rejection with an increase in area under the plasma concentration vs. time curve (AUC) of MPA, and to a lesser extent with predose trough plasma MPA concentrations; (6) increased incidence of side effects in patients with higher AUC of MPA; (7) a relationship between MPA concentration and activity as measured by suppression of DNA synthesis or expression of T cell activation markers, in vitro; (8) difficulty in assessing the clinical response to MMF therapy; (9) narrow therapeutic index of MPA; and (10) the significant consequences of therapeutic failure (rejection). [1][2][3][4][5] Most of the studies published to date have been carried out in renal and cardiac transplant patients.…”

“…(2) What is the therapeutic range to be achieved when MMF is used alone versus when it is used in combination with other agents? (3) What is the optimal therapeutic range for MPA early after transplantation compared with a later time after transplantation? (4) Does the trough MPA level provide a proper estimate of drug exposure, especially when it is more sensitive to enterohepatic recycling?…”