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

Albany College of Pharmacy, Albany, New York; Ordway Research Institute, Albany, New York; Pulmonary Associates, Phoenix, Arizona; and Theravance, Inc., South San Francisco, California

^* To whom correspondence should be addressed. Email: lodiset{at}acp.edu.

	Abstract

Background: Telavancin is an investigational bactericidal lipoglycopeptide with a multifunctional mechanism of action, as demonstrated against methicillin-resistant Staphylococcus aureus (MRSA). While the plasma pharmacokinetics have been described, drug penetration in the lung, measured by the epithelial lining fluid (ELF), remains unknown. Population modeling and Monte Carlo simulation were employed to estimate the ELF penetration of telavancin.

Methods: Plasma and ELF pharmacokinetic data were obtained from 20 healthy volunteers, and the pharmacokinetic samples were assayed with a validated liquid chromatography (LC)-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 9999 subjects was performed to calculate the ELF/plasma penetration ratios by estimating the AUC_ELF and free AUC_Plasma from zero to infinity (AUC_0-inf) after a single dose.

Results: After the Bayesian step, the overall fits of the model to the data were good and plots of predicted versus observed concentrations for plasma and ELF showed slopes and intercepts very close to the ideal values of 1.0 and 0.0, respectively. The median AUC_ELF/free AUC_Plasma penetration ratio was 0.73, and the 25^th and 75^th percentile value ratios were 0.43 and 1.24, respectively.

Conclusion: In non-infected lung tissue, the median AUC in ELF is approximately 75% of the free drug AUC in plasma.