1807. Interference of Oritavancin on Coagulation Tests as Assessed In vitro and in a Phase 1 Study of Normal Healthy Volunteers
Session: Poster Abstract Session: Antibacterial Safety
Saturday, October 29, 2016
Room: Poster Hall
Posters
  • Belley et al_1807_final.pdf (441.6 kB)
  • Background: Oritavancin (ORI) is a lipoglycopeptide (LG) antibiotic approved as a single-dose treatment of adults with acute bacterial skin and skin structure infections caused by gram-positive pathogens. As some LG and lipopeptide (LP) antibiotics are known to interfere with phospholipid (PL)-dependent coagulation tests (CT), we assessed the effects of ORI on common CT and determined the time-to-resolution (TtR) of test interference.

    Methods: For testing of clinical samples, plasma was obtained from normal healthy volunteers (NHV; n= 20) at defined time intervals following a 3h infusion of a single 1200 mg dose of ORI in a Phase 1 study. For in vitro testing, ORI was spiked into human plasma over a concentration range of 2 to 47 µg/ml. PL-dependent CT included prothrombin time (PT), activated partial thromboplastin time (APTT), Dilute Russell Viper Venom Test (DRVVT), activated clotting time (ACT), silica clot time (SCT) and activated Protein C Resistance (APCR). PL-independent CT included chromogenic anti-factor Xa (anti-FXa), thrombin time (TT) and an assay to diagnose heparin-induced thrombocytopenia (anti-heparin-PF4). The TtR of each test interference was the interval from the start of the ORI infusion to the time the result returned to the normal reference range.

    Results: Transient prolongation of PT, APTT, DRVVT, ACT and SCT occurred in plasma samples obtained from NHVs in the phase 1 study (table). Using ORI-spiked human plasma in vitro, prolongation of coagulation in the affected tests occurred in a concentration-dependent manner. ORI did not interfere with assays for APCR, anti-FXa, TT, or anti-heparin-PF4.

    Conclusion: Although ORI has no effect of the coagulation system, it can cause artificial elevations in some laboratory CT. Because of its single-dose regimen, the transient interference of ORI on these CT does not require further consideration beyond the specified TtR of test interference in contrast to some LG and LP antibiotics that require daily administration.
    Coagulation test Time-to-resolution (hours) of test interference in normal healthy volunteers that received a single 1200 mg infusion of oritavancin 
    Phospholipid-dependent
    PT 12
    APTT 120
    ACT 24
    SCT 18
    DRVVT 72
    APCR unaffected
    Phospholipid-independent
    Anti-FXa unaffected
    TT unaffected
    Anti-heparin-PF4 unaffected

    Adam Belley, Ph.D.1, Richard Robson, MBChB2, John Francis, PhD3, Dot Adcock, MD4, Stefan Tiefenbacher, PhD4, Christopher M. Rubino, Pharm.D.5, Greg Moeck, Ph.D.1, David Sylvester, BSc6, Michael Dudley, PharmD, FIDSA6 and Jeff Loutit, MBChB7, (1)Infectious Disease Care, The Medicines Company, Saint Laurent, QC, Canada, (2)Christchurch Clinical Studies Trust, Christchurch, New Zealand, (3)Florida Hospital Center for Thrombosis Research, Winter Park,, FL, (4)LabCorp, Englewood, CO, (5)Institute for Clinical Pharmacodynamics, Schenectady, NY, (6)Infectious Disease Care, The Medicines Company, San Diego, CA, (7)The Medicines Company, San Diego, CA

    Disclosures:

    A. Belley, The Medicines Company: Employee , Salary

    R. Robson, The Medicines Company: Investigator , Research support

    J. Francis, The Medicines Company: Consultant , Consulting fee

    D. Adcock, The Medicines Company: Research Contractor , Research support

    S. Tiefenbacher, The Medicines Company: Research Contractor , Research support

    C. M. Rubino, The Medicines Company: Research Contractor , Research support

    G. Moeck, The Medicines Company: Employee , Salary

    D. Sylvester, The Medicines Company: Employee , Salary

    M. Dudley, The Medicines Company: Employee , Salary

    J. Loutit, The Medicines Company: Employee , Salary

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