Therapeutic Monitoring of Mycophenolate in Transplantation: Is It Justified?

Mycophenolate mofetil (MMF) is the preferred antimetabolite in solid organ transplantation. It is a prodrug that undergoes pre-systemic metabolism to mycophenolic acid (MPA), the active drug moiety. MMF is typically administered as a fixed dose without routine monitoring of MPA concentrations. However, a role for therapeutic drug monitoring (TDM) of MPA has been suggested based on the drug's narrow therapeutic window and considerable between-subject variability. Dose-normalized MPA area under the concentration-time curve (AUC) has been observed to vary >= 10-fold. Some of this variability may be accounted for by patient variability in renal and liver function, serum albumin and haemoglobin levels, body mass, concomitant medication exposure and genetic polymorphisms in enzymes responsible for drug metabolism and transport, but much is unexplained. Widespread adoption of MPA TDM has been limited by the impracticality of full 0 to 12 hour AUC measurement (AUC(0-12)), poor correlation between pre-dose MPA concentration and AUC(0-12), ongoing questions regarding the utility of free versus total MPA measurements and lack of evidence correlating MPA exposure with clinical outcomes. Two recent randomized studies evaluating the role of MPA TDM in renal transplant recipients have reported conflicting results. Promising areas of ongoing study include use of Bayesian forecasting to predict MPA dosage and measurement of inosine monophosphate dehydrogenase activity. This review provides an overview of the pharmacokinetics of MMF in solid organ transplantation, and discusses the benefits and limitations of MPA monitoring. Areas that require additional research are identified.