Pharmacokinetic/pharmacodynamic evaluation of multidose oritavancin for prolonged durations of therapy

ABSTRACT Managing multidrug-resistant gram-positive infections is challenging, especially when prolonged therapy is needed for conditions like bacteremia, endocarditis, osteomyelitis, or other deep-seated infections. Oritavancin, a long-acting lipoglycopeptide, is increasingly used in these scenarios and offers an alternative to central catheter placement. However, despite its growing use for extended treatment, optimal dosing strategies and pharmacokinetic targets remain unclear. An in silico pharmacokinetic/pharmacodynamic simulation was performed to assess the predicted oritavancin concentration resulting from weekly and every 2-week dosing regimens. The simulations utilized a previously published model, which utilized pharmacokinetic sampling data from two single-dose, phase 3 clinical trials. A 100% free time above the MIC was utilized as the pharmacodynamic target. The Clinical and Laboratory Standards Institute breakpoint (0.12 µg/mL) and MIC90 (0.06 µg/mL) values for both Staphylococcus aureus and Enterococcus faecalis were utilized as benchmarks. Eighty-five percent protein binding was assumed. A six-dose regimen of 1,200 mg weekly is expected to maintain free plasma concentrations above the breakpoint for a median of 10.4 weeks (lower 5th percentile 9.6) and above the MIC90 for about 1.5 weeks longer, exceeding what is usually required for acute treatment of most infections. Alternatively, using a three-dose regimen of 1,200 mg every 2 weeks is expected to maintain free plasma concentrations above the breakpoint for a median of 8.4 weeks (lower 5th percentile 7.9), with trough values remaining therapeutic between doses. Every 2-week dosing strategies are expected to maintain therapeutic concentrations between doses. This strategy may be employed to reduce the cost of treatment and improve patient convenience.