Mycophenolate mofetil for solid organ transplantation: does the evidence support the need for clinical pharmacokinetic monitoring?
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.
Cox
Victoria C
VC
Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia, Canada.
Ensom
Mary H H
MH
D002986:Clinical Trials as Topic; D003657:Decision Making; D004305:Dose-Response Relationship, Drug; D016903:Drug Monitoring / Q000379:methods*; D006084:Graft Rejection / Q000276:immunology / Q000517:prevention & control; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D009173:Mycophenolic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000493:pharmacokinetics* / Q000627:therapeutic use; D016377:Organ Transplantation
D007166:Immunosuppressive Agents; D009173:Mycophenolic Acid