Oritavancin Pharmacokinetics and Bone Penetration in Rabbits

Abstract

The pharmacokinetics and bone concentrations of oritavancin were investigated after a single intravenous dose was administered to rabbits. The pharmacokinetic profile of oritavancin in rabbits showed that it is rapidly distributed to bone tissues, with concentrations remaining stable for up to 168 h, the last measured time point. Based on these findings, further evaluation of oritavancin for the treatment of infections in bone tissues is warranted. (2) and rapid concentration-dependent bactericidal activity in vitro against a variety of Gram-positive species, including drug-resistant enterococci, staphylococci, and streptococci (3). Oritavancin is characterized by a long half-life (4), which allows for the treatment of ABSSSI with a single dose of the drug (Orbactiv package insert [1]).S. aureus is the most common pathogen responsible for bone and joint infections (5-8); these infections often require long treatment durations with frequent dosing. The high level of activity of oritavancin against S. aureus (including MRSA) and its long half-life are characteristics that warrant further investigations for the treatment of infections caused by Gram-positive infection requiring long-term antibiotic therapy, such as bone and joint infections. This study was conducted to determine the systemic exposure of oritavancin in rabbits relative to human exposure and to evaluate the bone penetration of oritavancin after a humanized dose in rabbits. MATERIALS AND METHODSAntimicrobial agent. Oritavancin was manufactured and provided by The Medicines Company. Oritavancin powder was dissolved in 5% dextrose in water, mixed by vortexing for 1 min, filtered through a sterile 0.22-m filter, and stored at room temperature until administration. Oritavancin was administered as a 5-min intravenous infusion via the marginal ear vein using an indwelling catheter.Animals. Ten-to 12-week-old male New Zealand White rabbits (Charles River Laboratories, Saint-Constant, Canada) weighing 2.1 to 2.5 kg were used. The animal care and use practices in this study were in accordance with the guidelines and policies of the American Association of Laboratory Animal Care and the Canadian Council on Animal Care. All experimental protocols were approved by an institutional animal care and use committee.Pharmacokinetic study in serum. Twelve rabbits (n ϭ 3/dose) were administered 10, 15, 20, or 40 mg/kg of body weight of oritavancin. Blood samples were collected at 0.5, 3, 6, 12, and 24 h after dosing from each rabbit via the central ear artery. It is to be noted that blood collection at 12 h from animals receiving 40 mg/kg was inadvertently not performed.Pharmacokinetic study in bone. Twenty-one rabbits (n ϭ 3/time point) were administered a 20-mg/kg dose of oritavancin. This dose was selected subsequently to the pharmacokinetic study in serum, as it provided an exposure close to the 1,200-mg single dose in humans. Blood samples were collected at 0. 08,3,6,14,24, 48, and 168 h after dosing via the central ear artery. Late blood sampling at 168 h was sele...

Multiple‐Dose Oritavancin Evaluation in a Retrospective Cohort of Patients with Complicated Infections

“…Four patients were treated with oritavancin for osteomyelitis, and all reached a positive clinical outcome. A rabbit model supported the use of oritavancin in these patients by finding excellent bone penetration with a stable concentration over 168 hours following oritavancin administration …”

“…This activity against common pathogens makes oritavancin an attractive option for the treatment of noncellulitis indications. Further, the volume of distribution of oritavancin and penetration into invasive sites such as lung and bone are favorable for exploring its use in complicated infections …”

“…Further, the volume of distribution of oritavancin and penetration into invasive sites such as lung and bone are favorable for exploring its use in complicated infections. 10,11 The use of oritavancin in the treatment of complicated infections such as bacteremia, endocarditis, pneumonia, osteomyelitis, and surgical site infections is currently unknown, but the severity and high recurrence rates of these infections may require more than single-dose therapy. Case reports demonstrate that multiple doses of oritavancin are safe and effective in the treatment of vancomycin-resistant E. faecium (VRE) prosthetic valve endocarditis and methicillin-susceptible Staphylococcus aureus (MSSA) osteomyelitis.…”

Successful Treatment of Methicillin Susceptible Staphylococcus aureus Osteomyelitis with Oritavancin

“…Bone penetration of oritavancin has been evaluated after administration of a humanized dose in rabbits. 14 Oritavancin tissue-to-serum area under the curve (AUC) 0-168 ratio was 1.7 and 3.1 in bone matrix and bone marrow, respectively, representing higher bone penetration than previously reported for other antimicrobial agents such as linezolid, vancomycin, teicoplanin, and dalbavancin in animal studies. [15][16][17] To date, oritavancin has not been evaluated in experimental models of osteomyelitis.…”

“…We are unaware of previous reports of oritavancin therapy for osteomyelitis. Bone penetration of oritavancin has been evaluated after administration of a humanized dose in rabbits . Oritavancin concentrations were 10 μg/ml in serum for 24 hours after a single dose (several‐fold above the MIC for 90% of isolates [MIC 90 ] for S. aureus (0.06 μg/ml).…”