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Antimicrobial Agents and Chemotherapy, July 2008, p. 2300-2304, Vol. 52, No. 7
0066-4804/08/$08.00+0     doi:10.1128/AAC.01110-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Telavancin Penetration into Human Epithelial Lining Fluid Determined by Population Pharmacokinetic Modeling and Monte Carlo Simulation{triangledown}

Thomas P. Lodise Jr.,1,2* Mark Gotfried,3 Steven Barriere,4 and George L. Drusano2

Albany College of Pharmacy,1 Ordway Research Institute, Albany, New York,2 University of Arizona, Pulmonary Associates, Phoenix, Arizona,3 Theravance, Inc., South San Francisco, California4

Received 22 August 2007/ Returned for modification 8 November 2007/ Accepted 13 April 2008

Telavancin is an investigational bactericidal lipoglycopeptide with a multifunctional mechanism of action, as demonstrated against methicillin-resistant Staphylococcus aureus. While the plasma pharmacokinetics have been described, the extent of the penetration of the drug into the lung, measured by the epithelial lining fluid (ELF), remains unknown. Population modeling and Monte Carlo simulation were employed to estimate the penetration of telavancin into ELF. Plasma and ELF pharmacokinetic data were obtained from 20 healthy volunteers, and the pharmacokinetic samples were assayed by a validated liquid chromatography-tandem mass spectrometry technique. Concentration-time profiles in plasma and ELF were simultaneously modeled using a three-compartment model with zero-order infusion and first-order elimination and transfer. The model parameters were identified in a population pharmacokinetic analysis (BigNPAG). Monte Carlo simulation of 9,999 subjects was performed to calculate the ELF/plasma penetration ratios by estimating the area under the concentration-time curve (AUC) for the drug in ELF (AUCELF) and for the free drug in plasma (free AUCplasma) from zero to infinity after a single dose. After the Bayesian step, the overall fits of the model to the data were good, and plots of predicted versus observed concentrations in plasma and ELF showed slopes and intercepts very close to the ideal values of 1.0 and 0.0, respectively. The median AUCELF/free AUCplasma penetration ratio was 0.73, and the 25th and 75th percentile value ratios were 0.43 and 1.24, respectively. In uninfected lung tissue, the median AUCELF is approximately 75% of the free AUCplasma.

* Corresponding author. Mailing address: Albany College of Pharmacy, 106 New Scotland Avenue, Albany, NY 12208-3492. Phone: (518) 694-7292. Fax: (518) 694-7062. E-mail: lodiset{at}acp.edu

{triangledown} Published ahead of print on 21 April 2008.

Antimicrobial Agents and Chemotherapy, July 2008, p. 2300-2304, Vol. 52, No. 7
0066-4804/08/$08.00+0     doi:10.1128/AAC.01110-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





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