Model-informed dose optimization of mycophenolic acid in pediatric kidney transplant patients

We aimed to develop and evaluate a population PK model of mycophenolic acid (MPA) in pediatric kidney transplant patients to aid MPA dose optimization.

Data were collected from pediatric kidney transplant recipients from a Dutch academic hospital (Radboudumc, the Netherlands). Pharmacokinetic model-building and model-validation analyses were performed using NONMEM. Subsequently, we externally evaluated the final model using data from another academic hospital. The final model was used to develop an optimized dosing regimen.

Thirty pediatric patients were included of whom 266 measured MPA plasma concentrations, including 20 full pharmacokinetic (PK) curves and 24 limited sampling curves, were available. A two-compartment model with a transition compartment for Erlang-type absorption best described the data. The final population PK parameter estimates were K_tr (1.48 h^-1; 95% CI, 1.15-1.84), CL/F (16.0 L h^-1; 95% CI, 10.3-20.4), V_c/F (24.9 L; 95% CI, 93.0-6.71E25), V_p/F (1590 L; 95% CI, 651-2994), and Q/F (36.2 L h^-1; 95% CI, 9.63-74.7). The performance of the PK model in the external population was adequate. An optimized initial dose scheme based on bodyweight was developed. With the licensed initial dose, 35% of patients were predicted to achieve the target AUC, compared to 42% using the optimized scheme.

We have successfully developed a pharmacokinetic model for MPA in pediatric renal transplant patients. The optimized dosing regimen is expected to result in better target attainment early in treatment. It can be used in combination with model-informed follow-up dosing to further individualize the dose when PK samples become available.