Population Pharmacokinetics and Pharmacodynamics of Dalbavancin and C-Reactive Protein in Patients with Staphylococcal Osteoarticular Infections.

Abstract

Dalbavancin is increasingly used for the long-term treatment of chronic osteoarticular infections. A population pharmacokinetic/pharmacodynamic (PK/PD) analysis for assessing the relationship between dalbavancin exposure and C-reactive protein (C-RP) over time was conducted. Non-linear mixed-effect modeling was fitted to dalbavancin and C-RP concentrations. Monte Carlo simulations assessed the weekly percentage of C-RP reduction associated with different dosing regimens, starting from baseline to < 1mg/dL. A total of 45 patients were retrospectively included in the analysis. The PK of dalbavancin was described by a two-compartment model, and the PD of C-RP was described by an indirect turnover maximum inhibition model. The total dalbavancin concentration model estimate producing 50% of maximum C-RP production inhibition (IC50) was 0.70 mg/L. Monte Carlo simulations showed that in patients with staphylococcal osteoarticular infections targeting total dalbavancin concentrations at > 14.5 mg/L at any time point may achieve C-RP production inhibition over time in > 95% of patients. Based on this, the findings showed that a cumulative dose of 3000 mg administered in the first 3weeks may lead to a > 90% C-RP decrease versus baseline in approximately 5-6 weeks. In patients needing treatment prolongation, an additional 1500mg dose after this period may maintain C-RP concentrations < 1 mg/dL for other 3 weeks. A decrease in C-RP is related to dalbavancin exposure in osteoarticular infections. Targeting dalbavancin plasma concentrations above the efficacy threshold may be associated with effective treatment.