Individualisation of Mycophenolate Mofetil Therapy: Explaining variability in mycophenolic acid pharmacokinetics and introducing therapeutic

The prodrug mycophenolate mofetil contains the active compound mycophenolic acid (MPA), which has immunosuppressive properties. It is used to prevent acute rejection after solid organ transplantation. In renal transplantation, the dose recommendation for mycophenolate mofetil is 1000 mg twice daily for adult patients. This fixed dose strategy for mycophenolate mofetil is remarkable in the field of transplantation as most other immunosuppressive drugs are used in an individualised dose, often based on drug concentration measurements. During the use of mycophenolate mofetil in the past ten years, data have become available which provide four reasons to question the justification of a fixed mycophenolate mofetil dose. The first reason is the existence of a concentration-effect relationship: the risk for acute rejection is lower when exposure to MPA is higher. This has led to the adoption of a target exposure range for MPA area-under-the-curve (AUC0-12) values of 30 to 60 mg*h/L. The second reason is the large between-patient variability in MPA pharmacokinetics, reported to be more than 10-fold for MPA AUC0-12. The third reason is that MPA exposure increases over time after transplantation despite a fixed dose. Finally, exposure to MPA is significantly influenced by the use of several other drugs. The result of these four factors is that with the use of a standard dose of mycophenolate mofetil, an important subset of renal transplant recipients will have MPA exposure outside the target range, and may therefore be at risk for acute rejection or toxicity. Individualisation of the mycophenolate mofetil dose is likely to improve exposure to MPA and may optimise clinical outcome. The aim of this thesis was to develop recommendations about when and how to individualise the mycophenolate mofetil dose. Two hypotheses in this regard were addressed, formulated in chapter 1.2. The first was that demographic factors that contribute to the variability in the pharmacokinetics of MPA may serve as a rationale for mycophenolate mofetil dose individualisation (chapters 2.1 to 2.6, and 4.1). The second was that therapeutic drug monitoring of MPA provides a suitable tool for mycophenolate mofetil dose individualisation (chapters 3.1 and 3.2).

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