Une modelisation informatique pour une meilleure comprehension de la relation PK/PD: application a l'azithromycine dans le traitement de l'angine aiguee streptococcique et des exacerbations aiguees de la bronchite chronique

摘要

In order to illustrate the significance of pharmacokinetic/pharmacodynamic (PK/PD) parameters of azithromycin (AZM) in tonsillar and respiratory tract infections, we developed original simulation software. As area under the curve over 24 hours divided by the minimum inhibitory concentration (AUC_(24)/MIC)) and time over a 24-hour period that the drug concentration exceeds the MIC (t > MIC) are important predictors of the clinical efficacy of macrolides, our software calculates these indices for plasma, tonsil, epithelial lining fluid (ELF), lung tissue (LT) and alveolar macrophages (AM). For an MIC of 0.5 μg · mL~(-1), after administration of AZM 500mg daily for 3 days (tonsillitis) or AZM 500mg on day 1 and 250mg daily for the next 4 days (respiratory tract infections) to a 70kg subject, PK/PD parameters are as follows: 1. AUC_(24)/MIC (h) : 9.5 (plasma); 439 (tonsil); 57.5 (ELF); 439 (LT); 1354 (AM); 2. t > MIC is 24 hours in all tissues. Our simulation model illustrates the following: (ⅰ) AUC_(24)/MIC values are above the 25-30-hour threshold in S. pneumoniae infection; and (ⅱ) tissue concentrations exceed the MIC for 6 days after the last dose in ELF and for more than 2 weeks in tonsils, LT and AM.