Extended-duration dosing and distribution of dalbavancin into bone and articular tissue

Abstract

Dalbavancin is an intravenous lipoglycopeptide with activity against Gram-positive pathogens and an MIC90 for Staphylococcus aureus of 0.06 μg/ml. With a terminal half-life of >14 days, dosing regimens with infrequent parenteral administration become available to treat infectious diseases such as osteomyelitis and endocarditis that otherwise require daily dosing for many weeks. In order to support a rationale for these novel regimens, the pharmacokinetics over an extended dosing interval and the distribution of dalbavancin into bone and articular tissue were studied in two phase I trials and pharmacokinetic modeling was performed. Intravenous administration of 1,000 mg of dalbavancin on day 1 followed by 500 mg weekly for seven additional weeks was well tolerated and did not demonstrate evidence of drug accumulation. In a separate study, dalbavancin concentrations in cortical bone 12 h after infusion of a single 1,000-mg intravenous infusion were 6.3 μg/g and 2 weeks later were 4.1 μg/g. A two-dose, once-weekly regimen that would provide tissue exposure over the dalbavancin MIC for Staphylococcus aureus for 8 weeks, maximizing the initial exposure to treatment while minimizing the frequency of intravenous therapy, is proposed.

FIG 1

Mean dalbavancin plasma concentrations on day 1 (a) and at steady state (b).

FIG 2

Dalbavancin concentrations in plasma, bone, and related tissues. Semilog scatterplots: one skin concentration and eight synovial tissue concentrations were greater than the upper limit of quantification of the assay and do not appear in these plots.

FIG 3

Linear plot of the population mean predicted amount of dalbavancin in serum versus time, overlaid upon the observed data.

FIG 4

Linear plot of the population mean predicted amount of dalbavancin in bone versus time, overlaid upon the observed data.

FIG 5

Simulated mean concentration-time profiles with 1,500 mg i.v. on days 1 and 8 in plasma and bone (upper panels) and with 1,000 mg i.v. on day 1 and 500 mg i.v. weekly in plasma and bone (lower panels).