Population pharmacokinetic analysis identifies an absorption process model for mycophenolic acid in patients with renal transplant

Abstract

The pharmacokinetics (PKs) of mycophenolic acid (MPA) exhibit considerable complexity and large variability. We developed a population pharmacokinetic (popPK) model to predict the complex PK of MPA by examining an absorption model. Forty-two patients who had undergone renal transplantation were included in this study. popPK analysis, incorporating several absorption models, was performed using the nonlinear mixed-effects modeling program NONMEM. The MPA area under the concentration-time curve at 0–12 h (AUC0–12) was simulated using the final model to calculate the recommended dose. The PK of MPA was adequately described using a two-compartment model incorporating sequential zero- and first-order absorption with lag time. Total body weight, renal function (RF), and posttransplantation day (PTD) were included as covariates affecting MPA PK. The final model estimates were 7.56, 11.6 L/h, 104.0 L, 17.3 L/h, 169.0 L, 0.0453, 0.283, and 1.95 h for apparent nonrenal clearance, apparent renal clearance, apparent central volume of distribution, apparent intercompartmental clearance, apparent peripheral volume of distribution, absorption half-life, lag time, and duration of zero-order absorption, respectively. Simulation results showed that a dose regimen of 500–1000 mg twice daily is recommended during the early posttransplantation period. However, dose reduction could be required with increased PTD and decreased RF. The complex PK of MPA was explained using an absorption model. The developed popPK model can provide useful information regarding individual dosing regimens based on PTD and RF.