Development and Clinical Validation of Model-Informed Precision Dosing for Everolimus in Liver Transplant Recipients

Everolimus presents significant dosing challenges due to between- and within-patient pharmacokinetic variabilities. This study aimed to develop and validate a model-informed precision dosing strategy for everolimus in liver transplant recipients. The dosing strategy was initially developed using retrospective data, employing nonlinear mixed-effects modeling. The model included readily measurable covariates, body surface area, albumin, and tacrolimus trough concentration. The dosing strategy was subsequently validated in a prospective trial, recommending 1 to 1.75 mg dosages every 12 h, depending on covariates. Lower dosages were recommended for patients with lower body surface area and albumin with adjustments based on tacrolimus trough concentration. The estimated pharmacokinetic parameters (typical value ± standard error), apparent clearance (CL/F: 15.0 ± 0.5 L/h), and apparent volume of distribution (V_d/F: 862 ± 79.3 L) were refined using prospective clinical data from 20 patients, reducing interindividual variations. This research successfully developed and validated a population pharmacokinetic model for everolimus. The developed "dosE" web-based platform translates our pharmacokinetic model into a practical tool for healthcare providers, exemplifying the application of pharmaceutical research in clinical practice and potentially improving therapeutic outcomes in liver transplantation.