Program Schedule

398
Pharmacokinetics of dalbavancin (DAL) in bone and associated tissues in patients undergoing orthopedic surgical procedures

Session: Poster Abstract Session: PK/PD Studies
Thursday, October 9, 2014
Room: The Pennsylvania Convention Center: IDExpo Hall BC
Posters
  • Abstract Poster Dalbavancin BONE Final v.4.pdf (630.9 kB)
  • Background: DAL is lipoglycopeptide antibiotic which is a highly protein bound (93%) with a long elimination half-life in plasma. DAL exhibits activity against Gram-positive organisms, including MRSA, with an in vitro MIC90 of 0.06 mg/ml. The objective of this study was to characterize the PK of DAL in bone and associated tissues in patients undergoing joint surgery.

    Methods: Adults scheduled for joint surgery (N = 31) were administered 1 g of DAL infused over 30 minutes prior to scheduled surgery. Patients were assigned to 1 of 6 cohorts and had serial plasma PK samples collected up to 45 days post-dose plus 1 bone PK sample collected at 12, 24, 72, 168, 240 or 336 hr post dose. Samples were analyzed for DAL in plasma, synovial fluid, skin, cartilage and bone using LC-MS/MS. A population PK model was fit to plasma and bone PK data using NONMEM and covariate analysis was performed. Allometry was used to determine the total amount of bone tissue and to estimate the amount of DAL in bone. 

    Results:

    DAL concentrations in bone, synovial fluid, synovial tissue, and skin exceeded the DAL MIC90 against S. aureus of 0.06 mg/mL. DAL concentrations in bone appeared to remain relatively constant for a period of 14 days after a single dose. The mean bone:plasma AUC penetration ratio was 13.9%.

     

    Mean concentration ± SD

    (no. of samples)

    Tissue

    Hour 12

    Hour 24

    Hour 72

    Hour 168

    Hour 240

    Hour 336

    Plasma

    (mg/mL)

    85.3 ± 18.9

    (31)

    --

    --

    --

    --

    15.3 ± 4.1

    (31)

    Synovium

    (mg/g)*

    25.0 ± 0

    (3)

    17.9 ± 7.8

    (3)

    19.5 ± 4.9

    (3)

    19.2 ± 8.9

    (4)

    25.0 ± 0

    (2)

    15.9± 7.9

    (3)

    Synovial fluid (mg/mL)*

    22.9

    (1)

    27.4 ± 10.8

    (4)

    19.2 ± 4.9 (3)

    11.6 ± 3.3 (2)

    13.9 ± 1.0 (3)

    6.2 ± 1.7 (2)

    Bone

    (mg/g)

    6.3 ± 3.1 (5)

    5.0 ± 3.5

    (5)

    4.6 ± 3.8 (5)

    3.8 ± 2.7

     (5)

    3.7 ± 2.2

    (5)

    4.1 ± 1.6

     (5)

    Skin

    (mg/g)*

    19.4 ± 7.9

    (2)

    12.5 ± 6.5

    (3)

    13.8 ± 1.4

    (2)

    15.7 ± 1.0

    (2)

    21.6

    (1)

    13.8 ± 2.1

    (2)

    * Concentrations above the upper limit of quantification are reported as 25 µg/unit

    Conclusion: Dalbavancin distributes into bone and associated tissue, including synovium. Bone penetration was 13.9% based upon total drug AUC and the high degree of protein binding suggests that the overall penetration is high relative to free-drug plasma concentrations. This study demonstrates that dalbavancin accumulates in bone and supports further study in patients with osteomyelitis and prosthetic joint infections.

    James Baldassarre, MD1, Scott Van Wart, M.S.2, Alan Forrest, PharmD2,3, Christopher Rubino, Pharm D2 and Michael Dunne, MD1, (1)Durata Therapeutics, Branford, CT, (2)Institute for Clinical Pharmacodynamics, Latham, NY, (3)University at Buffalo School of Pharmacy and Pharmaceutical Sciences, Buffalo, NY

    Disclosures:

    J. Baldassarre, Durata Therapeutics: Employee, Salary

    S. Van Wart, Durata Therapeutics: Collaborator, Consulting fee

    A. Forrest, Durata Therapeutic: Consultant, Consulting fee

    C. Rubino, Durata Theraputics: Consultant, Consulting fee

    M. Dunne, Durata Therapeutics: Employee and Shareholder, Salary

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