Therapeutic Drug Monitoring of Mycophenolic Acid in Solid Organ Transplant Patients Treated With Mycophenolate Mofetil: Review of the Literature

Abstract

Mycophenolate mofetil (MMF) has conventionally been administered at a fixed dose without routinely monitoring blood levels of mycophenolic acid (MPA), the active metabolite. The contribution of therapeutic drug monitoring (TDM) during MMF therapy remains controversial. A literature review was performed to explore the usefulness of TDM for MPA in solid organ transplantation. In addition, emphasis was placed on the potential clinical benefits and limitations of TDM for MPA. Available studies have limitations and report conflicting results. Although early after transplantation MPA area under the curve might have predictive value for the risk of acute rejection, predose levels appear less reliable. With regard to MPA toxicity, most studies showed no correlation between MPA pharmacokinetics and adverse effects. TDM is hampered by several factors such as the considerable intra-subject variability of MPA pharmacokinetics and the increasing number of different drug combinations. Proposed target ranges are restricted to the early posttransplant period when MMF is used in combination with cyclosporine. The current review of the literature indicates no clear support for a substantial clinical benefit of TDM and more data from prospective randomized trials are needed.

Pharmacokinetics of oral mycophenolate mofetil in combination with CsA in dogs after nonmyeloablative allogeneic hematopoietic stem cell transplantation

“…17,18 For healthy adults half-lives of about 16-18 h were determined. 19,20 In consequence, similar MMF doses as used in SOT achieved lower AUC values in the range of 10-30 mg/ml h and C min levels o1 mg/ml. [5][6][7][14][15][16] In accordance with these clinical data we found in our study total MPA AUC 0À12 h and median blood trough levels below the recommended target ranges and shortened Table 2 Correlation coefficients (r) between MPA AUC 0-12 h and each MPA concentration Table 3 Pharmacokinetic parameters of total MPA after oral application of 20 mg/kg MMF in combination with 15 mg/kg CSA twice daily at different days after hematopoietic stem cell transplantation Pharmacokinetics of MMF following transplantation S Lange et al median half-life as well.…”

Hydroxamic Acid Derivatives of Mycophenolic Acid Inhibit Histone Deacetylase at the Cellular Level

“…The yields of 2 via acid chloride and subsequent treatment with hydroxylamine hydrochloride in the presence of Et 3 N (entries 1 and 2) were 10% and 19%, whereas that via mixed anhydride (entry 3) was improved to 38% (61% calculated yield based on the recovered starting material). MPHA (2) inhibited the enzymatic activity of HDAC at 1 mM in vitro (Table 2).…”

“…(E)-6-(1,3-Dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxo-5-isobenzofuranyl)-4-methyl-4-hexenohydroxamic acid (2). Ethylchloroformate (59.6 ml, 0.63 mmol) and Et 3 N (93 ml, 0.66 mmol) were added to a solution of 1 (100.0 mg, 0.31 mmol) in THF (2 ml) at 0 C, and the mixture was stirred for 45 min.…”

An inosine 5′-monophosphate dehydrogenase 2 single-nucleotide polymorphism impairs the effect of mycophenolic acid

“…Differences in the MPA area under the plasma concentration time curve in transplant recipients receiving the same standard dose of mycophenolate mofetil were reported to be up to 10-fold, and in baseline IMPDH activity among patients with end-stage renal disease, this difference was over eightfold. 9,10 The substantial variability of basal IMPDH activity and MPA effectiveness might be explained by variations within IMPDH genes or in gene expression. 5 Thus, this study was conducted to elucidate a possible role of frequent variants in the IMPDH2 gene in different responsiveness to MPA by testing their functional relevance in vitro in a lymphocyte proliferation assay, as well as measuring IMPDH activity in lymphocyte-enriched peripheral blood mononuclear cells.…”