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

Abstract

Background and objective: 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.

Methods: 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 < 1 mg/dL.

Results: 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 3 weeks may lead to a > 90% C-RP decrease versus baseline in approximately 5-6 weeks. In patients needing treatment prolongation, an additional 1500 mg dose after this period may maintain C-RP concentrations < 1 mg/dL for other 3 weeks.

Conclusions: 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.

Fig. 1

Prediction-corrected visual predictive check for the population (a) pharmacokinetic and (b) pharmacodynamic models. By default, three prediction intervals are displayed, one for each of the following percentiles of observed data: 10th, 50th and 90th percentiles. Prediction intervals are estimated across all simulated data and are displayed as colored areas (pink for the 50th percentile, blue for the 10th and 90th percentiles). Each prediction interval is computed with a level of 90%. The continuous blue lines indicate the 10th, 50th and 90th percentiles for observed data. C-RP C-reactive protein

Fig. 2

Relationship between dalbavancin concentration and extent of inhibition effect for C-RP production after 10,000 Monte Carlo simulations using the population values and between-subject variability from the PK/PD model. The solid and dashed lines represent the median and 90% prediction interval of the extent of the inhibition effect, respectively. The gray vertical dotted lines represent the IC₅₀ (0.70 mg/L) and the 95% percentile of the IC₅₀ (14.5 mg/L). C-RP C-reactive protein, IC₅₀ half maximal inhibitory concentration, PD pharmacodynamic, PK pharmacokinetic

Fig. 3

Percentage reduction of estimated median C-RP over time after administering a total dalbavancin dose of 3000 mg in the first 3 weeks in relation to different schedule regimens and classes of renal function. Horizonal dotted lines identify a 90% probability of C-RP reduction. In the eGFR 60–89 mL/min/1.73 m² class, the 1.5 g D1 + 1.5 g D8 group is overlaid to that of the 1.5 g D1 + 0.5 g D8 + 0.5 g D15 + 0.5 g D22 group. C-RP C-reactive protein, D day, eGFR estimated glomerular filtration rate

Fig. 4

Percentage reduction of estimated median C-RP over time after an initial total dalbavancin dose of 3000 mg in the first 3 weeks in relation to different schedule regimens followed by an additional 1500 mg dose at D43 in relation to different classes of renal function. Horizonal dotted lines identify a 90% probability of C-RP reduction. C-RP C-reactive protein, D day, eGFR estimated glomerular filtration rate