Variability in the pharmacokinetics of mycophenolic acid: Implications for therapeutic drug monitoring

Mycophenolate mofetil (MMF) is an immunosuppressive drug used to prevent rejection following solid organ transplantation. MMF was introduced in 1995 with a recommended fixed-dose regimen of 1 g twice daily. Nowadays, dose individualization using therapeutic drug monitoring (TDM) of the area under the concentration-time curve from 0 to 12 hours postdose (AUC0-12) of the active compound, mycophenolic acid (MPA), is advocated to optimize the treatment. The recommended target range for the MPA AUC0-12 in renal transplant recipients is 30-60 mg*h/L. A practical and suitable manner of determining the MPA AUC0-12 are abbreviated AUC measurements, in which the AUC0-12 is estimated by a limited sampling strategy. In renal transplant recipients, it has been shown that limited sampling strategies estimate MPA AUC0-12 with sufficient accuracy and precision. The aim of this thesis was to further explain the differences in the pharmacokinetics of MMF seen between renal transplant recipients, investigate the validity of these results in other populations, or when different formulations are used, and to describe the effects of these results on individualization of the MMF treatment. In Chapter 1 of this thesis, an overview of the pharmacokinetics of MPA in renal transplant recipients and the added value of TDM are discussed. MPA is a highly protein bounded drug, which binds reversibly to albumin. The free fraction is thought to be responsible for the immunosuppressive effect of MPA. Cyclosporine comedication, low plasma albumin level, and impaired renal function are associated with a decrease in total MPA AUC, but the unbound concentration is hardly affected. The effect of these covariates on total and unbound MPA concentrations is clarified in Chapter 2.1. The effect of MMF dose on the pharmacokinetics of MPA is evaluated in Chapter 2.2. In Chapter 2.3 the differences in the pharmacokinetics of MPA between adult and pediatric renal transplant recipients are examined. Besides solid organ transplantation, MMF is increasingly used to prevent graft-versus-host disease following hematopoietic stem cell transplantation and for treatment of autoimmune diseases. TDM may be a valuable tool to optimize MMF therapy in these patients as well. The differences in the pharmacokinetics of MPA between renal transplant recipients and hematopoietic stem cell transplant patients and patients with autoimmune diseases and the consequences of these differences for TDM are reported in Chapter 3. To prevent gastrointestinal adverse events, which are frequently seen during MMF treatment, enteric-coated mycophenolate sodium (EC-MPS) was developed. EC-MPS and MMF are both prodrugs of MPA, and showed similar efficacy and safety profiles. In Chapter 4, the pharmacokinetic profile of MPA is compared following administration of EC-MPS and MMF.

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