Population Pharmacokinetic Analysis of Immediate-Release Oral Tacrolimus Co-administered with Mycophenolate Mofetil in Corticosteroid-Free Adult Kidney Transplant Recipients.

BACKGROUND AND OBJECTIVE: Tacrolimus is the mainstay calcineurin inhibitor frequently administered with mycophenolic acid with or without corticosteroids to prevent graft rejection in adult kidney transplant recipients. The primary objective of this study was to develop and evaluate a population pharmacokinetic model characterizing immediate-release oral tacrolimus co-administered with mycophenolate mofetil (a pro-drug of mycophenolic acid) in adult kidney transplant recipients on corticosteroid-free regimens. The secondary objective was to investigate the effects of clinical covariates on the pharmacokinetics of tacrolimus, emphasizing the interacting effects of mycophenolic acid.

METHODS: Population modeling and evaluation were conducted with Monolix (Suite-2018R1) using the stochastic approximation expectation-maximization algorithm in 49 adult subjects (a total of 320 tacrolimus whole-blood concentrations). Effects of clinical variables on tacrolimus pharmacokinetics were determined by population covariate modeling, regression modeling, and categorical analyses.

RESULTS: A two-compartment, first-order absorption with a lag-time, linear elimination, and constant error model best represented the population pharmacokinetics of tacrolimus. The apparent clearance value for tacrolimus was 17.9 l/h (6.95% relative standard error) in our model, which is lower compared with similar subjects on corticosteroid-based therapy. The glomerular filtration rate had significant effects on the apparent clearance and central compartment volume of distribution. Conversely, mycophenolic acid did not affect the apparent clearance of tacrolimus.

CONCLUSION: We have developed and internally evaluated a novel population pharmacokinetic model for tacrolimus co-administered with mycophenolate mofetil in corticosteroid-free adult kidney transplant patients. These findings are clinically important and provide further reasons for conducting therapeutic drug monitoring in this specific population.