Seonghae Yoon (1), Jongtae Lee (1), Sang-il Min (2), Jongwon Ha (2), In-jin Jang (1)
(1) Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Korea, (2) Department of Surgery, Seoul National University College of Medicine and Hospital, Seoul, Korea
Objectives: Tacrolimus is an immunosuppressive agent, largely used in kidney transplantation. The objectives of this study were to develop the population pharmacokinetic (PK) model of once-daily tacrolimus formulation (Advagraf®) and twice-daily tacrolimus formulation (Prograf®) in stable pediatric kidney transplant recipients and to identify significant covariates that influence on tacrolimus PK.
Methods: Thirty-four stable pediatric kidney transplant recipients were enrolled in open-label, parallel study. Enrolled patients received twice-daily tacrolimus formulation for 7 days. On the morning of day 8, the regimen was converted to once-daily tacrolimus formulation on a 1:1 for their total daily dose and was remained for the last of the study. Blood samples were collected on study day 7, 14, 21(trough concentration) and 28 (after dosing adjustment). Nonlinear Mixed-effects modeling (NONMEM, ver. 7.2) was used to determine the typical population PK parameters and their inter-individual and intra-individual variability. The first-order conditional estimation (FOCE) with interaction method was used to fit the plasma concentration-time data. Basic goodness-of-fit diagnostics and visual predictive checks were used to evaluate the adequacy of the model fit and prediction.
Results: The PK of tacrolimus was best described by a two-compartment model with first-order absorption. In the final pharmacokinetic model, centered hematocrit and cytochrome P450 3A5 were significant covariates on apparent clearance (CL/F). For apparent central volume (V2/F), centered age was a significant covariate. Diurnal variation in absorption kinetics of tacrolimus was described by the difference of absorption rate constant.
Conclusions: Once-daily tacrolimus formulation and twice-daily tacrolimus formulation showed different PK characteristics. The final PK parameter estimates and covariates (hematocrit, CYP3A5, age) can be applied to determine the optimal dosage regimens of tacrolimus in pediatric kidney transplantation patients.
References:
[1] J.B. Woillard, B. C. M. de Winter, N. Kamar. Population pharmacokinetic model and Bayesian estimator for two tacrolimus formulations – twice daily Prograf® and once daily Advagraf®, Br J Clin Pharmacol 2011; 71(3):391-402
Reference: PAGE 22 (2013) Abstr 2843 [www.page-meeting.org/?abstract=2843]
Poster: Covariate/Variability Model Building