Therapeutic Monitoring of Mycophenolate Mofetil

Mycophenolate mofetil (MMF) has become the single most used immunosuppressant in solid-organ transplantation. Despite a well-documented relationship and efficacy (in terms of acute rejection prophylaxis) and exposure to mycophenolic acids (MPA) as measured by area under the curve (AUC), excellent results have been achieved using a fixed-dosage regimen. In the past several years, there has been an increased interest in the utility of monitoring MPA concentrations to both increase efficacy and decrease toxicity, particularly in many current drug minimization protocols.

MMF is morpholinoethyl ester of MPA, a potent and reversible inhibitor of inosine monophosphate dehydrogenase (IMPDH), isoform 2 (1). MPA originally was discovered from Penicillium brevicompactum and related fungi in the late 19th century, and its major activity on IMPDH first was reported in 1969 (2). MPA was developed as an immunosuppressant by Syntex in 1980s to complement existing immunosuppressive agents, including calcineurin inhibitor, azathioprine, and corticosteroids (3). IMPDH became a target for immunosuppression because lymphocytes depend on the de novo guanosine nucleotide synthesis pathway for DNA synthesis and cell division (3). Because other cell types, including neurons, depend primarily on the alternative salvage pathway for DNA synthesis, MPA selectively inhibits the proliferation of human T and B lymphocytes. Since the 1990s, when large, double-blind, randomized trials in kidney transplant recipients (4–6) showed the efficacy of MMF in preventing early acute rejection, in combination with cyclosporine (CsA) and prednisone, MMF has been used widely as a part of various combination regimens of immunosuppressive agents. To appreciate fully the complexities and controversies involved in therapeutic monitoring, one must have a substantial understanding of the pharmacokinetics and pharmacodynamics of MPA. This review covers the basic pharmacology of MMF and then discusses the data that are available on the utility of monitoring of MPA concentrations.