[Software modeling for better understanding of pharmacokinetic-pharmacodynamic relationships: application to azithromycin in the treatment of streptococcal tonsillitis and in acute exacerbation fo chronic bronchitis]]

Abstract

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 (AUC24/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 microgram.mL-1, after administration of AZM 500 mg daily for 3 days (tonsillitis) or AZM 500 mg on day 1 and 250 mg daily for the next 4 days (respiratory tract infections) to a 70 kg subject, PK/PD parameters are as follows: AUC24/MIC (h): 9.5 (plasma); 439 (tonsil); 57.5 (ELF); 439 (LT); 1354 (AM); t > MIC is 24 hours in all tissues. Our simulation model illustrates the following: (i) AUC24/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.