A target-based population pharmacokinetic and pharmacodynamic analysis for intra-articular dosing regimen optimization of vancomycin in patients with periprosthetic joint infections.

Aims: Although intra-articular vancomycin has demonstrated satisfactory outcomes for periprosthetic joint infection (PJI), dose and dosing frequency remain largely empirical. This study aimed to develop a target-based population pharmacokinetics (PK) model to predict local vancomycin exposure, and to evaluate the efficacy and safety of various regimens in patients with PJI. Methods: Patients with PJI who received intravenous (IV) infusion or intra-articular injection of vancomycin were included. Population PK analysis was performed using nonlinear mixed effects modelling. Monte Carlo simulations were used to assess pharmacodynamic target attainment against Results: A total of 450 plasma and synovial fluid samples from 161 patients with PJI were analyzed. The pharmacokinetics of vancomycin in synovial fluid were best described by a two-compartment joint model linked to a central plasma compartment. Creatinine clearancesignificantly affected systemic clearance, while age influenced the penetration from synovial fluid to the central compartment. Simulations suggested that intra-articular dosing of 500 mg once daily was sufficient for targets against Conclusion: The intra-articular population PK model accurately characterized vancomycin concentrations in plasma and synovial fluid, supporting optimized intra-articular dosing regimens in patients with PJI according to renal function and age.