OBJECTIVE To systematically evaluate published population pharmacokinetic(PopPK) models of daptomycin regarding their structural characteristics, covariate effects, and validation strategies, and identify key factors that affect its pharmacokinetics variability, and to provide a theoretical basis for individualized dosing in special populations.

METHODS A comprehensive literature search was performed in PubMed, Embase, Cochrane Library, Web of Science, CNKI, WanFang, and VIP databases from inception until September 4, 2025. Two investigators independently screened studies and extracted data from eligible PopPK studies of daptomycin in adults and the extracted data were analyzed.

RESULTS Twenty-four studies were included. The two-compartment model(n=18) and NONMEM software(n=15) were most frequently used. Typical estimates of daptomycin for clearance(CL) and volume of central compartment(V_c) ranged from 0.229 to 1.02 L·h⁻¹ and 0.95 to 151 L, respectively. Renal function(creatinine clearance or estimated glomerularfiltration rate) and body weight were the primary covariates for CL, while V_c was significantly associated with body weight, sex, body composition(eg. fat-free mass), and disease status. Bootstrap and visual predictive check were common validation methods.

CONCLUSION Renal function, body weight, and disease status are the primary sources of pharmacokinetic variability for daptomycin. Patients with these factors should receive individualized dosing regimens based on suitable PopPK models. Future efforts should focus on increasing sample sizes, strengthening multi-center validation, and further investigating the impact of genetic factors and special populations on pharmacokinetic behavior.