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Antimicrobial Agents and Chemotherapy, October 2009, p. 4422-4428, Vol. 53, No. 10
0066-4804/09/$08.00+0     doi:10.1128/AAC.00231-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Oritavancin Population Pharmacokinetics in Healthy Subjects and Patients with Complicated Skin and Skin Structure Infections or Bacteremia{triangledown}

Christopher M. Rubino,1,2* Scott A. Van Wart,1,2 Sujata M. Bhavnani,1,2 Paul G. Ambrose,1,2 Jill S. McCollam,3,{dagger} and Alan Forrest1,2

Institute for Clinical Pharmacodynamics, Ordway Research Institute, Inc., Albany, New York,1 SUNY at Buffalo, School of Pharmacy and Pharmaceutical Sciences, Buffalo, New York,2 Targanta Therapeutics, Cambridge, Massachussetts3

Received 18 February 2009/ Returned for modification 18 May 2009/ Accepted 14 July 2009

Oritavancin is a novel glycopeptide antimicrobial agent with potent in vitro activity against a wide variety of gram-positive bacteria, including multidrug-resistant strains of staphylococci and enterococci. A population pharmacokinetic model was developed to describe the disposition of oritavancin with data from a pooled population of phase 1 healthy subjects and phase 2 and 3 patients with complicated skin and skin structure infections or Staphylococcus aureus bacteremia. In addition, the potential influence of factors such as the subject's age, gender, and clinical laboratory measures on oritavancin disposition was evaluated. Oritavancin was administered as both single- and multiple-dose intravenous (i.v.) infusions in fixed doses ranging from 100 to 800 mg or weight-based doses ranging from 0.02 to 10 mg/kg of body weight, with infusion durations ranging from 0.13 to 6.5 h across all studies. The most robust fit to the data (n = 6,290 oritavancin plasma concentrations from 560 subjects) was obtained using a three-compartment model with zero-order i.v. infusion and first-order elimination. The model was parameterized using total clearance (CL), volume of central compartment (Vc), distributional clearances from the central to both the first and second peripheral compartments, and volumes of distribution for both the first and second peripheral compartments. Weight and study phase (phase 1 versus phase 2/3) were identified as significant predictors of the interindividual variability in CL, while body surface area and age were significant for Vc. These results suggest that dose modification may be warranted in patients weighing >110 kg. However, the mild nature of the observed relationships for Vc suggest that dosing adjustments are not necessary for elderly patients.

* Corresponding author. Mailing address: Institute for Clinical Pharmacodynamics, Ordway Research Institute, Inc., 43 British American Blvd., Latham, NY 12110. Phone: (518) 429-2604. Fax: (518) 429-2601. E-mail: CRubino-ICPD{at}ordwayresearch.org

{triangledown} Published ahead of print on 27 July 2009.

{dagger} Present address: Ortho-McNeil Janssen Scientific Affairs, LLC, Raritan, NJ.

Antimicrobial Agents and Chemotherapy, October 2009, p. 4422-4428, Vol. 53, No. 10
0066-4804/09/$08.00+0     doi:10.1128/AAC.00231-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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