Seongmee Jeong1, Hyeong-Jun Jo2, Kyoung-Bin Ryu2, Jayoung Hong2, Kwan Soo Kim2, Seong-jun Yang2, Corresponding author Soyoung Lee1, Corresponding author Jung-woo CHAE1,3,4, Corresponding author Hwi-yeol Yun1,3,4
1College of Pharmacy, Chungnam National University, 2Clinical Research Division, National Institute of Food and Drug Safety Evaluation, Ministry of Food and Drug Safety,, 3Department of Bio-AI convergence, Chungnam National University, 4Senior Health Convergence Research Center, Chungnam National University
Objective: Sirolimus has been currently used off-label for pediatric patients with vascular anomalies and Pharmaceuticals and Medical Devices Agency (PMDA) has approved a dosing regimen for these patients, which is adjusted to maintain a specific range based on the trough concentration in recent. However, standardized dosage regimen still has been controversial for pediatric population, especially another races. This study aims to provide safe usage information for sirolimus in pediatric patients with vascular malformations using population pharmacokinetic model Methods: Before the model development, systematic review was conducted to collect retrospective population pharmacokinetic models of sirolimus in pediatric patients with vascular anomalies and the collected model was reproduced to confirm its reliability using visual/numerical predictive checks. In addition, data were obtained from prospective and retrospective studies involving 28 pediatric patients, with 7 subjects in the prospective study and 21 subjects in the retrospective study. The prospective study data were used to develop the base model, while the retrospective study data were used for the base model validation. Population pharmacokinetics of sirolimus was analyzed using NONMEM software (version 7.5) with the first-order conditional estimation method with interaction (FOCE INTER). Assessment of model was applied through general modeling building criteria and bootstrap stepwise covariate modeling method was conducted to identify clinically relevant covariates. Simulations were performed for various scenarios to determine the optimal dosing regimen for maintaining the trough concentration within a specific range. Results: Total 4 models, collected by literatures, were reproduced in implementation of size/maturation function, laboratory test, and formulation effect and its information would be used as prior information for model building steps. For model development, a total of 213 samples (free drug concentration) were used for analysis. Pharmacokinetics of sirolimus was best described by a 2-compartment model based on prospective study. In addition, external validation was performed using retrospective study, and it was confirmed that the model well explained the data. Accordingly, the model was implemented by maturation function using postmenstrual age (PMA), allometrically scaled body weight to account for size differences and hemoglobin as a covariate on clearance. No significant effect was observed for covariates such as bilirubin, CYP genotype, formulation, and treatment duration. Simulation was conducted to suggest a safe dosing regimen for the patients, with a dosing regimen of 0.01 – 0.1 mg/kg once daily for 1 month, the trough concentration was maintained within the range of 5~15 ng/mL. Conclusions: In this study, a robust and reliable pharmacokinetic model of sirolimus was developed for the pediatric patients with vascular anomalies. Optimal dosing regimens should be suggested based on individual growth of pediatrics and hemoglobin levels.
[1] Greene, Arin K et al. “Risk of vascular anomalies with Down syndrome.” Pediatrics vol. 121,1 (2008): e135-40. doi:10.1542/peds.2007-1316
Reference: PAGE 33 (2025) Abstr 11482 [www.page-meeting.org/?abstract=11482]
Poster: Drug/Disease Modelling - Paediatrics