Abstract
Background: Tacrolimus is a cornerstone immunosuppressant in kidney transplantation, but its narrow therapeutic index and marked inter-patient variability complicate dose optimization. Conventional therapeutic drug monitoring (TDM) relies on empirical adjustments that often overlook individual pharmacokinetics. Machine learning (ML) offers a precision dosing alternative by integrating diverse clinical and biochemical variables into predictive models. Methods: We retrospectively analyzed 1351 data points from 87 kidney transplant patients at Eunpyeong St. Mary's Hospital (April 2019-November 2023). Clinical, demographic, and laboratory information, including tacrolimus trough levels and dosing history, were extracted from electronic medical records. Four predictive models-XGBoost, CatBoost, LightGBM, and a multilayer perceptron (MLP)-were trained to forecast next-day tacrolimus concentrations, and model serum creatinine level performance was evaluated using R-squared (R(2)), mean absolute error (MAE), and root-mean-squared error (RMSE). An ensemble model with weighted soft voting was applied to enhance predictive accuracy, and model interpretability was assessed using SHapley Additive exPlanations (SHAP). Results: The ensemble model achieved the best overall performance (R(2) = 0.6297, MAE = 1.0181, RMSE = 1.2999), outperforming all individual models, whereas the MLP model showed superior predictive power among single models, reflecting the significance of nonlinear interactions in tacrolimus pharmacokinetics. SHAP analysis highlighted prior tacrolimus levels, cumulative dose, renal function markers (eGFR level, serum creatinine level), and albumin concentration as the most influential predictors. Conclusions: We present a robust ML-based algorithm for tacrolimus dose optimization in hospitalized kidney transplant recipients. By improving predictions of tacrolimus concentrations, the model may help reduce inter-patient dose variability and lower the risk of nephrotoxicity, supporting safer and more individualized immunosuppressive management. This approach advances AI-driven precision medicine in transplant care, offering a pathway to safer and more effective immunosuppression.