Population Pharmacokinetics of Dalbavancin and Dosing Consideration for Optimal Treatment of Adult Patients with Staphylococcal Osteoarticular Infections

Abstract

<i>Background:</i> Dalbavancin is gaining interest in the treatment of complex osteoarticular (OA) infections.<i>Objective:</i> 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.<i>Methods:</i> 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 <i>f</i>AUC_24h/MIC against <i>S. aureus</i> (>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%.<i>Results:</i> 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 <i>S. aureus</i> at the most effective PK/PD target for a period ranging 3-to-9 weeks. <i>Conclusion</i>: 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.