Population pharmacokinetics of dalbavancin and dosing consideration for optimal treatment of adult patients with staphylococcal osteoarticular infections

Abstract

Background: Dalbavancin is gaining interest in the treatment of complex osteoarticular (OA) infections.Objective: To conduct a population pharmacokinetic analysis of dalbavancin in a prospective cohort of adult patients with Gram-positive OA infections and to identify optimal dosing regimens for long term-treatment.Methods: Non-linear mixed-effects modelling was performed with Monolix. Monte Carlo simulations were performed with six dalbavancin regimens (1500mg at day 1; 1000mg at day 1 plus 500mg at day 8; 1500mg at day1 and 8; 1500mg at day1 and 8 plus 500, 1000 or 1500mg at day 36) to assess the PTA of three pharmacodynamic target of fAUC_24h/MIC against S. aureus (>27.1, 53.3 and 111.1). Cumulative fraction of response (CFR) was calculated against MIC distribution of both MRSA and MSSA as well. Desirable PTAs and CFRs were ≥90%.Results: Fifteen patients provided 120 plasma concentrations. Most (73.3%) had prosthetic joint infections. Clinical cure rate was 87%. A two-compartment model with linear elimination well described the data. No covariate was retained in the final model. Pharmacokinetic dalbavancin estimates were 0.106L/h for CL and 36.4L for V_ss The tested dosing regimens granted desirable CFRs against S. aureus at the most effective PK/PD target for a period ranging 3-to-9 weeks. Conclusion: Giving a two 1500mg dosing regimen of dalbavancin one week apart may ensure efficacy against both MSSA and MRSA up to 5 weeks in patients with OA infections. Clinical assessment at that time may allow for considering whether or not an additional dose should be administered for prolonging effective treatment.

FIG 1

Diagnostic plot for the final population pharmacokinetic model. Shown are observed versus population-predicted concentrations (left) and individual-predicted concentrations (right) in plasma. Solid lines refer to linear regression between observed and predicted concentrations. Dashed lines are the identity lines between observed and predicted concentrations.

FIG 2

Visual predictive check (VPC) of dalbavancin plasma concentration versus time for the final model. The continuous lines indicate the 10th, 50th, and 90th percentiles for observed data, while the shaded gray areas represent 90% prediction intervals from the corresponding percentiles calculated from simulated data.

FIG 3

Simulated dalbavancin plasma concentration versus time profiles of six different dosing regimens (1,500 mg at day 1; 1,000 mg at day 1 and 500 mg at day 8; 1,500 mg at days 1 and 8; 1,500 mg at day 1, 1,500 mg at day 8, and 500 mg at day 36; 1,500 mg at day 1, 1,500 mg at day 8, and 1,000 mg at day 36; and 1,500 mg at day 1, 1,500 mg at day 8, and 1,500 mg at day 36). The solid line is the simulated median concentration. The dashed lines are the 5th, 25th, 75th, and 95th percentiles of simulated concentrations.

FIG 4

Probabilities of target attainment (PTAs) of achieving a fAUC_24h/MIC value of 27.1 with six different dosing regimens (1,500 mg at day 1; 1,000 mg at day 1 and 500 mg at day 8; 1,500 mg at days 1 and 8; 1,500 mg at day 1, 1,500 mg at day 8, and 500 mg at day 36; 1,500 mg at day 1, 1,500 mg at day 8, and 1,000 mg at day 36; and 1,500 mg at day 1, 1,500 mg at day 8, and 1,500 mg at day 36). The histograms are the MIC distribution frequencies of 801 Staphylococcus aureus isolates yielded from bone and joint infections in 78 European and U.S. hospitals between 2011 and 2016 (14). The dotted lines identify desirable PTA (≥90%).

FIG 5

Probabilities of target attainment (PTAs) of achieving a fAUC_24h/MIC value of 53.3 with six different dosing regimens (1,500 mg at day 1; 1,000 mg at day 1 and 500 mg at day 8; 1,500 mg at days 1 and 8; 1,500 mg at day 1, 1,500 mg at day 8, and 500 mg at day 36; 1,500 mg at day 1, 1,500 mg at day 8, and 1,000 mg at day 36; and 1,500 mg at day 1, 1,500 mg at day 8, and 1,500 mg at day 36). The histograms are the MIC distribution frequencies of 801 Staphylococcus aureus isolates yielded from bone and joint infections in 78 European and U.S. hospitals between 2011 and 2016 (14). The dotted lines identify desirable PTA (≥90%).

FIG 6

Probabilities of target attainment (PTAs) of achieving a fAUC_24h/MIC value of 111.1 with six different dosing regimens (1,500 mg at day 1; 1,000 mg at day 1 and 500 mg at day 8; 1,500 mg at days 1 and 8; 1,500 mg at day 1, 1,500 mg at day 8, and 500 mg at day 36; 1,500 mg at day 1, 1,500 mg at day 8, and 1,000 mg at day 36; and 1,500 mg at day 1, 1,500 mg at day 8. and 1,500 mg at day 36). The histograms are the MIC distribution frequencies of 801 Staphylococcus aureus isolates yielded from bone and joint infections in 78 European and U.S. hospitals between 2011 and 2016 (14). The dotted lines identify desirable PTA (≥90%).