A TARGET-BASED POPULATION PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSIS FOR INTRA-ARTICULAR DOSING REGIMEN OPTIMIZATION OF VANCOMYCIN IN PATIENTS WITH PERIPROSTHETIC JOINT INFECTIONS

Aim 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 infusion or intra-articular injection of vancomycin were included. Population PK analysis was performed using nonlinear mixed effects modeling. Given the biofilm-associated nature of PJI, Monte Carlo simulations were conducted based on the minimum biofilm eradication concentration (MBEC) to assess pharmacodynamic target attainment against Staphylococcus species and to evaluate vancomycin-associated safety risks. 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 clearance significantly 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 Staphylococcus aureus and Staphylococcus epidermidis, whereas other coagulase negative staphylococci required more intensive regimens, including 250 or 500 mg every 12 hours or 1000 mg once daily. For patients with severe renal impairment, intra-articular administration alone provided adequate systemic exposure, and concomitant intravenous administration was not recommended. 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. Acknowledgements This study was supported by Clinical Trials from the Affiliated Drum Tower Hospital, Medical School of Nanjing University (No. 2022-LCYJ-PY-41) and the Jiangsu Pharmaceutical Association Research Fund (No. 202495072)