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Antimicrobial Agents and Chemotherapy, May 2003, p. 1700-1706, Vol. 47, No. 5
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.5.1700-1706.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Pharmacodynamics of Oritavancin (LY333328) in a Neutropenic-Mouse Thigh Model of Staphylococcus aureus Infection

Carole J. Boylan,1* Kristina Campanale,1 Philip W. Iversen,1 Diane L. Phillips,1 Michael L. Zeckel,1 and Thomas R. Parr Jr.2*

Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana,1 Embiosis Pharmaceuticals, Carlsbad, California2

Received 29 April 2002/ Returned for modification 12 October 2002/ Accepted 4 February 2003

The pharmacokinetics and pharmacodynamics of oritavancin (LY333328), a glycopeptide antibiotic with concentration-dependent bactericidal activity against gram-positive pathogens, in a neutropenic-mouse thigh model of Staphylococcus aureus infection were studied. Plasma radioequivalent concentrations of oritavancin were determined by using [14C]oritavancin at doses ranging from 0.5 to 20 mg/kg of body weight. Peak plasma radioequivalent concentrations after an intravenous dose were 7.27, 12.56, 69.29, and 228.83 µg/ml for doses of 0.5, 1, 5, and 20 mg/kg, respectively. The maximum concentration of drug in serum (Cmax) and the area under the concentration-time curve (AUC) increased linearly in proportion to the dose. Neither infection nor neutropenia was seen to affect the pharmacokinetics of oritavancin. Intravenous administration resulted in much higher concentrations in plasma than the concentrations obtained with subcutaneous administration. Single-dose dose-ranging studies suggested a sigmoid maximum effect (Emax) dose-response relationship, with a maximal effect evident at single doses exceeding 2 mg/kg. The oritavancin dose (stasis dose) that resulted in a 24-h colony count similar to the pretreatment count was 1.53 (standard error [SE], 0.35) mg/kg. The single oritavancin dose that resulted in 50% of maximal bacterial killing (ED50) was 0.95 (SE, 0.20) mg/kg. Dose fractionation studies suggested that single doses of 0.5, 1, 2, 4, and 16 mg/kg appeared to have greater bactericidal efficacy than the same total dose subdivided and administered multiple times during the 24-h treatment period. When using an inhibitory Emax model, Cmax appears to correlate better with bactericidal activity than do the time during which the concentration in plasma exceeds the MIC (T>MIC) and AUC. These data suggest that optimal oritavancin dosing strategies will require regimens that favor high Cmax concentrations rather than long periods during which unbound concentrations in plasma exceed the MIC.

* Corresponding author. Mailing address: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46284. Phone: (317) 276-9056. Fax: (317) 433-3888. E-mail: Baylan_Carole{at}Lilly.com.

Antimicrobial Agents and Chemotherapy, May 2003, p. 1700-1706, Vol. 47, No. 5
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.5.1700-1706.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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