Significant Effects of Renal Function on Mycophenolic Acid Total Clearance in Pediatric Kidney Transplant Recipients with Population Pharmacokinetic Modeling

Abstract

Background and objectives: Mycophenolic acid (MPA) is an immunosuppressant commonly prescribed in pediatric kidney transplantation to prevent graft rejection. Large variabilities in MPA plasma exposures have been observed in this population, which could result in severe adverse effects. The majority of the MPA pharmacokinetic data have been reported in adult populations, whereas information in pediatric patients is still very limited. The objective of this study was to establish a novel, nonlinear mixed-effects model for MPA and investigate the clinical variables affecting MPA population pharmacokinetics in pediatric kidney transplant recipients.

Methods: Data were collected retrospectively from pediatric kidney transplant patients (≤ 18 years when MPA concentrations were initially collected; on oral administration of mycophenolate mofetil) in Calgary, Alberta, Canada. Nonlinear mixed-effect modeling was conducted using stochastic approximation expectation-maximization in Monolix 2021R2 (Lixoft SAS, France) to determine population pharmacokinetic estimates, interindividual variabilities, and interoccasional variabilities. Covariate models were constructed using the Model Proposal function in Monolix in conjunction with a systematic stepwise inclusion/elimination protocol. The best model was selected based on objective function values, relative standard errors, goodness-of-fit plots, prediction-corrected visual predictive checks, and numerical predictive checks.

Results: A total of 50 pediatric kidney transplant patients (25 female) with 219 MPA plasma concentration-time profiles were included. The average age (± standard deviation) and posttransplant time for the sample population were 12.8 ± 4.8 years and 762 ± 1160 days, respectively. The majority of study subjects (i.e., > 85% based on all occasions) were co-administered tacrolimus. A two-compartment, first-order absorption with lag time and linear elimination structural model with lognormal distributed proportional residual errors best described the MPA concentration-time data. The absorption rate constant (2.52 h^-1 or 0.042 min^-1), lag time (0.166 h or 9.96 min), volumes of distributions of the central (22.8 L) and peripheral (216 L) compartments, and intercompartment clearance (17.6 L h^-1 or 0.293 L min^-1) were consistent with literature values; whereas total MPA clearance (0.72 L h^-1 or 0.012 L min^-1) was relatively reduced, likely due to the general lack of cyclosporine interactions and the stabilized graft functions from significantly longer posttransplant time in our sample population. Of the clinical variables tested, only estimated glomerular filtration rate (eGFR) was identified a significant covariate affecting total MPA clearance with a positive, exponential relationship. The final population pharmacokinetic model was successfully evaluated/validated using a variety of complementary methods.

Conclusion: We have successfully constructed and validated a novel population pharmacokinetic model of MPA in pediatric kidney transplant patients. A positive, nonlinear relationship between eGFR and total MPA clearance identified in our model is likely attributed to multiple concurrent mechanisms, which warrant further systematic investigations.