Value of therapeutic drug monitoring of MMF therapy in pediatric transplantation.

Therapeutic drug monitoring (TDM) is desirable whenever the desired drug effect cannot be predicted from a given dose, or when it is necessary to find a balance between the efficacy and toxicity of the drug. Children and adolescents particularly benefit from TDM, because dosing requirements are often not studied in the same detail as in adults. Also, drug-drug interactions are frequent. The gold standard for assessment of drug exposure is the area-under-the-curve (AUC) for a full pharmacokinetic profile. TDM for mycophenolic acid (MPA) is less well established. Monitoring of trough levels does not suffice because of enterohepatic recirculation of MPA after formation of its main metabolite, a glucoronide termed MPA-G. However, abbreviated sampling schemes specific to mycophenolate mofetil (MMF) correlate well with the AUC for MPA. Cyclosporine interacts with MPA by inhibiting the multidrug resistance-associated protein 2 (MRP2). Higher MPA concentrations result in a decreased two h concentration of cyclosporine, while higher cyclosporine exposure results in a lower MPA exposure. There are no drug interactions between tacrolimus and MPA, and lower doses of MMF are required in combination with tacrolimus. Steroids may induce the clearance of MPA, which could account in part for the increasing MPA exposure following transplantation. TDM has allowed for dosing recommendations of MMF in children, which could lead to improved efficacy and minimization of toxicities. It is important that these provisional target levels are validated in prospective studies. The above points clearly indicate that there is a role for TDM of MPA in pediatric transplant recipients.