An interspecies extrapolation of the pharmacokinetics of telavancin, a rapidly bactericidal, concentration-dependent antibiotic

Abstract

1. Telavancin is an intravenous lipoglycopeptide antibiotic active against many Gram-positive pathogens via inhibition of bacterial cell wall synthesis and disruption of bacterial membrane function.

2. Non-compartmental pharmacokinetic parameters of telavancin (clearance [Cl], steady-state volume of distribution [Vss], area under the concentration curve [AUC], and elimination half-life [t_1/2]) were determined for five preclinical species (mice, rats, rabbits, dogs, and monkeys). Interspecies scaling was applied to predict the corresponding parameters in humans and compare retrospectively with observed values.

3. Plasma concentrations of single doses of telavancin declined monoexponentially in all species with half-lives between 1.2 and 2.4 h. The pharmacokinetics of telavancin was demonstrated to be dose-proportional in rabbits and gender-independent in monkeys.

4. Application of the simple allometric equation (Y = aW^b) resulted in a good correlation between predicted and observed values of Vss in humans. Application of a modified allometric equation that includes brain weight (Cl × BW = aW^b) resulted in a good correlation between predicted and observed values of Cl, AUC, and t_1/2 in humans.

5. These data suggest that interspecies scaling may be useful to predict pharmacokinetic parameters of telavancin in humans.

Keywords::

• Allometric equation
• interspecies scaling
• allometric scaling

Acknowledgements

This study was conducted by Theravance, Inc. The authors thank Stacy M. Adams and Julie D. Seroogy, former employees of Theravance, Inc., for assistance with this work. Editorial support, including writing assistance, was provided by Ed Parr, PhD, a medical writer at Envision Scientific Solutions, and was funded by Astellas Pharma Global Development, Inc.

Declaration of interest

The authors are former employees and stockholders of Theravance, Inc.