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

Dalbavancin is gaining interest in the treatment of complex osteoarticular (OA) infections. We aimed to conduct a population pharmacokinetic analysis of dalbavancin in a prospective cohort of adult patients with OA infections caused by Gram-positive organisms and to identify optimal dosing regimens for long-term treatment. Nonlinear mixed-effects modeling was performed with Monolix. Monte Carlo simulations were performed with six dalbavancin regimens (1,500 mg at day 1; 1,000 mg at day 1 plus 500 mg at day 8; 1,500 mg at days 1 and 8; and 1,500 mg at days 1 and 8 plus 500, 1,000, or 1,500 mg at day 36) to assess the probability of target attainment (PTA) of three pharmacodynamic targets of area under the concentration-time curve for the free, unbound fraction of a drug at 24 h/MIC (fAUC(24h)/MIC) against Staphylococcus aureus (>27.1, 53.3, and 111.1). The cumulative fraction of response (CFR) was calculated against the MIC distribution of both methicillin-resistant S. aureus (MRSA) and methicillin-susceptible S. aureus (MSSA). Desirable PTAs and CFRs were ≥90%. Fifteen patients provided 120 plasma concentrations. Most (73.3%) had prosthetic joint infections. The 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 0.106 liter/h for total body clearance (CL) and 36.4 liter for volume of distribution at steady state(V(ss)). The tested dosing regimens granted desirable CFRs against S. aureus at the most effective pharmacokinetic/pharmacodynamic (PK/PD) target for a period ranging 3 to 9 weeks. Giving a regimen of two 1,500-mg doses of dalbavancin 1 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 an additional dose should be administered for prolonging effective treatment.