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0091270008321273v1
48/9/1063    most recent
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QUANTITATIVE CLINICAL PHARMACOLOGY

Pharmacokinetic-Pharmacodynamic Modeling of Dalbavancin, a Novel Glycopeptide Antibiotic

James A. Dowell, PhD, Beth P. Goldstein, PhD, Mary Buckwalter, MS, Martin Stogniew, PhD and Bharat Damle, PhD

From Vicuron Pharmaceuticals, a wholly owned subsidiary of Pfizer, Inc, and Pfizer, Inc, New York. Dr. James Dowell is a member of the American College of Clinical Pharmacology.

Dalbavancin is a novel glycopeptide with a 2-dose, once-weekly dosing regimen that is being developed for the treatment of complicated skin and skin structure infections caused by gram-positive bacteria. Monte Carlo simulations were performed for dalbavancin using population pharmacokinetic data and minimum inhibitory concentrations (MICs) for clinical trial isolates. The time-dependent target was the maintenance of free drug concentrations above the MIC for 14 days (t > MIC). The concentration-dependent target was an area under the concentration-time curve (AUC)/MIC ratio of approximately 1000 for Staphylococcus aureus and 100 for Streptococcus sp. These targets were used to estimate susceptibility breakpoints for dalbavancin. For S aureus, the estimated susceptibility breakpoint was ≤0.5 µg/mL using AUC14 days/MIC and ≤1 µg/mL using t > MIC. For Streptococcus sp, the estimated susceptibility breakpoint was at least 2 µg/mL. Because dalbavancin MIC90s for these species are well below these values, the analysis supports the use of once-weekly dosing regimens of dalbavancin in the treatment of complicated skin and skin structure infections.

Key Words: Dalbavancin • Monte Carlo simulations • pharmacodynamics • pharmacokinetics • susceptibility

Address for reprints: Bharat Damle, PhD, Director, Clinical Pharmacology, Pfizer Global Research and Development, 685 3rd Avenue, New York, NY 10017; e-mail: bharat.damle{at}pfizer.com.


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