Pharmacokinetic/Pharmacodynamic Modeling for Concentration-Dependent Bactericidal Activity of a Bicyclolide, Modithromycin

ABSTRACT The aim of this study was to develop a pharmacokinetic (PK)/pharmacodynamic (PD) model of a bicyclolide, modithromycin, to explain its concentration-dependent bactericidal activity based on the drug–bacterium interaction model that we developed. We have already reported the applicability of model to the time-dependent activity of β-lactams, and we further applied the model to the concentration-dependent activity in this study. In vitro time-kill data of modithromycin, telithromycin, and clarithromycin against Staphylococcus aureus , Haemophilus influenzae , and treptococcus pneumoniae were used for the modeling. An effect compartment model was incorporated into our original model to explain the time lag between PK and PD profiles. Also, a turnover model for reversible reduction of efficacy was incorporated to explain the regrowth. The developed model well described the time-kill profiles for each drug–bacterium combination. The estimated parameter related to efficacy strongly correlated with minimum inhibitory concentration (MIC), and the simulated bacterial counts at 24 h strongly correlated with both the ratio of the area under the concentration–time curve to MIC (AUC/MIC) and the ratio of the maximum concentration to MIC ( C max /MIC). These results suggested that the proposed model can be applied to both concentration-dependent and time-dependent bactericidal kinetics, and would be useful for predicting the bactericidal activity of modithromycin. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:1288–1297, 2014