title: 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.
authors.affiliation: Durata Therapeutics, Inc., Branford, Connecticut, USA mdunne@duratatx.com.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Dunne
authors.affiliation: Durata Therapeutics, Inc., Branford, Connecticut, USA.
authors.forename: Sailaja
authors.initials: S
authors.lastname: Puttagunta
authors.affiliation: PRACS Institute, Ltd., Fargo, North Dakota, USA.
authors.forename: Craig R
authors.initials: CR
authors.lastname: Sprenger
authors.affiliation: Institute for Clinical Pharmacodynamics, Latham, New York, USA.
authors.forename: Chris
authors.initials: C
authors.lastname: Rubino
authors.affiliation: Institute for Clinical Pharmacodynamics, Latham, New York, USA.
authors.forename: Scott
authors.initials: S
authors.lastname: Van Wart
authors.affiliation: Durata Therapeutics, Inc., Branford, Connecticut, USA.
authors.forename: James
authors.initials: J
authors.lastname: Baldassarre
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001842:Bone and Bones / Q000378:metabolism*; D002358:Cartilage, Articular / Q000378:metabolism*; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D008875:Middle Aged; D012867:Skin / Q000378:metabolism; D013582:Synovial Fluid / Q000378:metabolism; D017334:Teicoplanin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D014018:Tissue Distribution; D055815:Young Adult
chemical_list: D000900:Anti-Bacterial Agents; D017334:Teicoplanin; C469289:dalbavancin