Advancing Daptomycin Precision Dosing Through Evaluation of Published Population Pharmacokinetic Models and Development of a Dosing Tool

Xi Xie,1,* Cheng Qian,2,* Sonia Luque,3– 5 Li Liu,6 Jiayu Chen,2 Carla Comajuan Mendoza,3,4 Luisa Sorli,3,4 Huamin Yuan,1 Chen Ma,2 Lin Ren,7 Nuo Xu,2 Gehang Ju,8,9 Xiao Zhu,2 Xin Liu2 1Department of Clinical Laboratory, Hunan Prevention and Treatment Institute for Occupational Diseases, Affiliated Prevention and Treatment Institute for Occupational Diseases of University of South China, Changsha, People’s Republic of China; 2Department of Clinical Pharmacy and Pharmacy Administration, School of Pharmaceutical Sciences, Fudan University, Shanghai, People’s Republic of China; 3Infectious Pathology and Antimicrobials Research Group (IPAR), Institute Hospital Del Mar d’Investigacions Mèdiques (IMIM), Barcelona, Spain; 4Pharmacy Department, Hospital del Mar, Barcelona, Spain; 5CIBER of Infectious Diseases (CIBERINFEC CB21/13/0002), Institute of Health Carlos III, Madrid, Spain; 6The Second People’s Hospital of Hunan Province (Brain Hospital of Hunan Province), Changsha, People’s Republic of China; 7Department of Pharmacy, The First Affiliated Hospital of Soochow University, Soochow, People’s Republic of China; 8Institute of Big Data, Central South University, Changsha, People’s Republic of China; 9Hunan Key Laboratory for Bioanalysis of Complex Matrix Samples, Changsha Duxact Biotech Co., Ltd, Changsha, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xiao Zhu; Xin Liu, Department of Clinical Pharmacy and Pharmacy Administration, School of Pharmaceutical Sciences, Fudan University, Shanghai, 201203, People’s Republic of China, Email [email protected]; [email protected]: Daptomycin is an important antibiotic against multidrug-resistant Gram-positive infections, but its wide interindividual variability and narrow therapeutic window pose challenges for optimal dosing. Population pharmacokinetic (PopPK) models provide a quantitative framework for precision dosing, yet a systematic evaluation of existing models and their clinical application method remains lacking.Methods: Model structures, demographic characteristics, and covariate effects were systematically summarized from previously published papers. Predictive performance was compared through simulations in virtual populations with varying renal function. Monte Carlo simulations were performed to evaluate the probability of target attainment (PTA; AUC24h/MIC ≥ 666) and the probability of toxicity (Cmin ≥ 24.3 mg/L). Furthermore, an open-access precision dosing tool was developed based on maximum a posteriori Bayesian estimation using representative model structure and parameters.Results: Eighteen PopPK studies were included in this analysis. Renal function was the most frequently identified covariate influencing clearance. Model comparisons revealed variability in predicting exposure and PTA. Simulations indicated that patients with impaired renal function face a higher risk of exceeding the toxicity threshold, even at moderate doses. The developed Shiny-based tool enables real-time estimation of AUC and Cmin, integration of therapeutic drug monitoring data, and individualized dose adjustment.Conclusion: This study provides a comprehensive evaluation of daptomycin PopPK models and translates these findings into a practical precision dosing tool. This work enhances understanding of interindividual variability of daptomycin and offers clinicians a scientifically grounded resource to optimize daptomycin therapy in diverse patient populations.Keywords: population pharmacokinetic, precision dosing, daptomycin, renal impairment