Population Pharmacokinetics and Limited Sampling Strategy of Mycophenolate Mofetil for Patients in Early Period After Kidney Transplantation.

Background: Mycophenolate mofetil (MMF) is widely used as an immunosuppressant in kidney transplantation. The pharmacokinetics (PK) of its active metabolite, mycophenolic acid (MPA), exhibit significant inter- and intra-individual variability. The early post-operative period is crucial for renal function recovery, and MPA exposure is linked to acute rejection. Due to the difficulty of implementing intensive sampling, limited sampling strategies (LSSs) are clinically important for MMF therapeutic drug monitoring for early-stage kidney transplant patients.

Methods: Demographic data, MPA plasma drug concentrations, and laboratory results for 137 patients in early period after kidney transplantation (within 30 days after surgery) were retrospectively analyzed. A population pharmacokinetic (PPK) model for MMF was developed using nonlinear mixed-effects modeling to assess the impact of covariates on the PK characteristics of MPA. Individualized initial dosing regimens were proposed based on Monte Carlo simulations. Using virtual population data, LSSs were developed through multiple linear regression (MLR), Bayesian estimation, and machine learning (ML).

Results: A two-compartment model with first-order absorption with a lag time and first-order elimination best described the PK data of MPA. Sex and weight were identified as significant covariates for CL/F and Vc/F, respectively. The recommended initial dose for male patients was 0.75 or 1 g twice daily, while for female patients, it was 0.5 or 0.75 g twice daily. The Bayesian estimation demonstrated the lowest prediction error among the LSSs approaches.

Conclusion: A PPK model and LSSs for MMF in Chinese kidney transplant patients in the early post-operative period were successfully developed, providing a valuable reference for MMF therapeutic drug monitoring.