Development and\nClinical Validation of Model-Informed\nPrecision Dosing for Everolimus in Liver Transplant Recipients

Everolimus presents significant dosing challenges due\nto between-\nand within-patient pharmacokinetic variabilities. This study aimed\nto develop and validate a model-informed precision dosing strategy\nfor everolimus in liver transplant recipients. The dosing strategy\nwas initially developed using retrospective data, employing nonlinear\nmixed-effects modeling. The model included readily measurable covariates,\nbody surface area, albumin, and tacrolimus trough concentration. The\ndosing strategy was subsequently validated in a prospective trial,\nrecommending 1 to 1.75 mg dosages every 12 h, depending on covariates.\nLower dosages were recommended for patients with lower body surface\narea and albumin with adjustments based on tacrolimus trough concentration.\nThe estimated pharmacokinetic parameters (typical value ± standard\nerror), apparent clearance (CL/<i>F</i>: 15.0 ± 0.5\nL/h), and apparent volume of distribution (V<sub>d</sub>/<i>F</i>: 862 ± 79.3 L) were refined using prospective clinical data\nfrom 20 patients, reducing interindividual variations. This research\nsuccessfully developed and validated a population pharmacokinetic\nmodel for everolimus. The developed “dosE” web-based\nplatform translates our pharmacokinetic model into a practical tool\nfor healthcare providers, exemplifying the application of pharmaceutical\nresearch in clinical practice and potentially improving therapeutic\noutcomes in liver transplantation.