A machine learning framework for precision dosing of daptomycin across diverse disease states

ABSTRACT The large pharmacokinetic variability of daptomycin across disease states poses a challenge for individualized dosing. Conventional population pharmacokinetic (PopPK) models are often limited to specific conditions, lacking generalizability. This study used a machine learning (ML) framework to predict daptomycin exposure and guide dose optimization across heterogeneous populations. Nine published PopPK models were used to generate 90,000 simulated profiles across patients with infections and/or patients treated with renal transplantation and/or renal replacement therapy. Seven ML algorithms were trained to predict the 24 h area under the concentration–time curve (AUC 0–24 ). Model performance was evaluated using statistical metrics and clinical scenario assessments, and comparison with PopPK models. External validation was conducted with real-world data. CatBoost demonstrated the highest predictive accuracy, identifying dose, creatinine clearance, disease state, and weight as key predictors. The validation cohort comprised 20 patients with infections (501 concentration measurements) and 19 patients receiving renal replacement therapy (513 concentration measurements). In infected patients, the prediction error of AUC 0–24 was reduced by 60.1% compared with existing PopPK models (root mean square error [RMSE], 141 vs 353 mg·h/L; mean absolute prediction error, 23.5% vs 58.1%). The ML model correctly classified 75.0% of patients into the appropriate clinical AUC categories (<666, 666–939, and >939 mg·h/L), outperforming PopPK models (average overall accuracy: 30.0%). In patients undergoing renal replacement therapy, ML also improved performance (RMSE, 197 vs 218 mg·h/L; overall accuracy, 52.6% vs 31.6%). The ML model demonstrated accurate prediction of steady-state daptomycin AUC in heterogeneous clinical populations and was successfully validated using real-world data. By enabling accurate pre-treatment exposure prediction, it provides a flexible and clinically useful pathway toward precision dosing of daptomycin.