Population Pharmacokinetic Approach to Evaluate Current Recommended Dose of Tacrolimus on Korean Pediatric Liver Transplant Patients
Authors: Jeon Jiyeon , Choi Youjoung , Yun Hwi-yeol , Lee Soyoung , CHAE Jung-Woo 
Published: February 2025

Objectives: Tacrolimus has narrow therapeutic window, drug monitoring to minimize toxicities is required for patients. Although tacrolimus is frequently used in liver transplant, pediatric monitoring is challenging due to their high inter- and intra- individual variabilities. There are limited number of pediatric studies on tacrolimus model, and those models did not include size and maturation functions. The primary objective of this study was to develop a population pharmacokinetic model for Korean pediatrics who had liver transplant and starting tacrolimus therapy. In addition, we aimed to evaluate the current recommended dose using the final population pharmacokinetic model.Methods: A total of 842 plasma concentrations were collected from pediatric liver transplant patients who followed by tertiary university Hospital. The population pharmacokinetic model’s parameters were estimated using nonlinear-mixed effect modeling (NONMEM) incorporating the size and maturation function to explain the pediatric growth characteristics. Potential covariates were tested using the stepwise covariate modeling (SCM) method to identify clinically significant covariates in the patient population. Model evaluation were done using goodness of fit plot (GOF), prediction-corrected predictive check (pcVPC) and bootstrap. Simulation studies based on various scenarios targeting the covariates were performed to appropriateness of current recommended dose and optimize the dose recommendation if needed. Results: There were thirty-six patients included in the study and 1-compartment model with size function with total bilirubin (TB) for clearance (CL) and blood urea nitrogen (BUN) for volume of distribution (Vd) was found to be the most appropriate model to describe population pharmacokinetic parameters. As the simulation results showed that currently recommended dose’s Ctrough level at the day 3 and 7, when patients will reach steady state concentration, is mostly safe for pediatrics. Although Ctrough levels at day 3 and 7 were within therapeutic index in all age groups, children and adolescents with normal TB and BUN level could result in higher Ctrough level when given higher dose at day 30. Conclusions: Population pharmacokinetic model was developed for tacrolimus on Korean pediatric patients with liver transplant. Developed model can be used to predict Ctrough level in patients. Our model’s simulation showed current dosing recommendation for liver transplant Korean pediatric patients is appropriate in most cases, while lower dose could be preferred as initial dosing to prevent toxicities.Citations: [1] Back, H. M., et al. "Application of Size and Maturation Functions to Population Pharmacokinetic Modeling of Pediatric Patients." Journal of Pediatric Pharmacology and Therapeutics, vol. 11, no. 6, 2019.[2] De Nicolò, A., et al. "Monitoring Tacrolimus Concentrations in Whole Blood and Peripheral Blood Mononuclear Cells: Inter- and Intra-Patient Variability in a Cohort of Pediatric Patients." Frontiers in Pharmacology, vol. 12, 2021, p. 750433. DOI: 10.3389/fphar.2021.750433.[3] Meirelles Junior, R. F., et al. "Liver Transplantation: History, Outcomes and Perspectives." Einstein (Sao Paulo), vol. 13, no. 1, 2015, pp. 149-152.[4] Tacrolimus (Oral Route). Mayo Clinic, n.d., https://www.mayoclinic.org/drugs-supplements/tacrolimus-oral-route/proper-use/drg-20068314. Accessed 17 Jan. 2024.