PII-079 - POPULATION PHARMACOKINETIC MODELING OF EVEROLIMUS AND INDIVIDUALIZED DOSING DEPENDING ON PROMISING COVARIATES IN LIVER TRANSPLANT RECIPIENTS.

J. Lee, I. Kim, K. Seo, S. Hong, J. Oh; Seoul National University, Seoul, Republic of Korea.

Background: Everolimus is licensed for liver transplantation, but has a narrow therapeutic range. In this study, we aimed to develop a population PK model of everolimus in Korean adult liver transplantation patients and evaluate the factors that can affect the PK of everolimus.

Methods: From June 2015 to February 2021, data were gathered from patients who received everolimus after liver transplantation. Everolimus dosage and its concentration data, demographic data, transplant surgery data, and co-medication data were collected retrospectively. Afterward, we created the population PK model using NONMEM (version 7.5.0). The final model validation was performed using bootstrap and visual predictive check. Finally, we performed the model-based simulation to investigate the optimal dose to achieve the target trough concentrations.

Results: One hundred liver transplant patients' trough concentrations totaled 1,130. One-compartment model was selected as a base model. After stepwise covariate modelling process, body surface area (BSA), albumin (ALB), and tacrolimus (TAC) level were selected as covariates. BSA increased the clearance, while TAC level showed the opposite effect. ALB both increased the clearance and volume of distribution. The final model estimated population PK parameters (typical value ± standard error) as follows: apparent clearance (CL/F: 14.7±4.1 L/h), apparent volume of distribution (857±10.3 L). The optimal daily dose to achieve the target trough concentration ranged between 1~1.75 mg bid depending on the covariate.

Conclusion: A population PK model for everolimus was successfully established in Korean adult liver transplantation patients. In addition, BSA, ALB, and TAC level came out to be promising covariates for everolimus PK parameters, indicating that individualized drug adjustment is required.