Takayuki Katsube (1), Toshihiro Wajima (1), Yoshinori Yamano (2), Yoshitaka Yano (3)
(1) Clinical Research Department, Shionogi & Co., Ltd., Japan, (2) Medicinal Research Laboratories, Shionogi & Co., Ltd., Japan, (3) Education and Research Center for Clinical Pharmacy, Kyoto Pharmaceutical University, Japan
Objectives: The aim of this study was to develop a pharmacokinetic/pharmacodynamic (PK/PD) model of a bicyclolide, modithromycin, to explain its concentration-dependent bactericidal activity against Staphylococcus aureus, Haemophilus influenzae and Streptococcus pneumoniae based on the drug-bacterium interaction model [1].
Methods: We have already developed a PK/PD model to explain the time-dependent bactericidal activity of β-lactams [1-4]. In this study, the model is extended to explain the concentration-dependent bactericidal activity and was applied to in vitro time-kill data of modithromycin, telithromycin and clarithromycin. An effect compartment model was incorporated into our original model [1] to explain the time delay between pharmacokinetics and pharmacodynamics. A turnover model for reversible reduction of drug efficacy was also incorporated to explain the re-growth.
Results: The model adequately described the time-kill profiles for each drug-bacterium combination. The estimated model parameters related to drug efficacy strongly correlated with MIC, and the simulated bacterial counts at 24 hours strongly correlated with both ratios of area under concentration-time curve to MIC (AUC/MIC) and ratios of maximum drug concentration to MIC (Cmax/MIC). Based on the results, simulations of bactericidal activity of modithromycin in patients could be performed.
Conclusions: These results suggested that the proposed drug-bacterium interaction model can be applied to both concentration-dependent and time-dependent bactericidal kinetics, and would be useful for predicting the bactericidal activity of modithromycin.
References:
[1] Yano Y, Oguma T, Nagata H, Sasaki S. Application of logistic growth model to pharmacodynamic analysis of in vitro bactericidal kinetics. J Pharm Sci. 1998. 87: 1177-1183.
[2] Katsube T, Yano Y, Yamano Y, Munekage T, Kuroda N, Takano M. Pharmacokinetic- pharmacodynamic modeling and simulation for bactericidal effect in an in vitro dynamic model. J Pharm Sci. 2008. 97: 4108-4117.
[3] Katsube T, Yamano Y, Yano Y. Pharmacokinetic-pharmacodynamic modeling and simulation for in vivo bactericidal effect in murine infection model. J Pharm Sci. 2008. 97: 1606-1614.
[4] Katsube T, Yano Y, Wajima T, Yamano Y, Takano M. Pharmacokinetic / pharmacodynamic modeling and simulation to determine effective dosage regimens for doripenem. J Pharm Sci. 2010. 99: 2483-2491.
Reference: PAGE 22 (2013) Abstr 2692 [www.page-meeting.org/?abstract=2692]
Poster: Infection