title: In vitro pharmacokinetic and pharmacodynamic evaluation of S-013420 against Haemophilus influenzae and Streptococcus pneumoniae.
abstract: The pharmacokinetic (PK)/pharmacodynamic (PD) parameters and the antibacterial activity of S-013420, a novel bicyclolide, against Haemophilus influenzae and Streptococcus pneumoniae, including macrolide-resistant isolates, were investigated using an in vitro PD model. Various time-concentration curves were artificially constructed by modifying the PK data obtained in phase I studies. The activity against H. influenzae was evaluated using two parameters, that is, the area above the killing curve (AAC) and the viable cell reduction at 24 h. The relationships between the antibacterial activity of S-013420 and the three PK/PD parameters were investigated by fitting the data to the sigmoid maximum effective concentration model. The square of the correlation coefficient (R(2)) values for AAC versus the area under the concentration-time curve from 0 to 24 h (AUC(0-24))/MIC, the peak concentration (C(max))/MIC, and the cumulative percentage of a 24-h period that the drug concentration exceeded the MIC under steady-state PK conditions (%T(MIC)) were 0.92, 0.87, and 0.49, respectively. The R(2) values for viable cell reduction at 24 h versus AUC(0-24)/MIC, C(max)/MIC, and %T(MIC) were 0.93, 0.61, and 0.56, respectively. These results demonstrated that AUC(0-24)/MIC is the most significant parameter for evaluation of the antibacterial activity of S-013420. The values of AUC(0-24)/MIC required for maximum and static efficacy were 10.8 and 9.63, respectively, for H. influenzae and 16.3 to 22.3 and 4.66 to 9.01, respectively, for S. pneumoniae. This analysis is considered useful for determining the AUC value at the infection site, which would be required for efficacy in clinical use.
authors.affiliation: Discovery Research Laboratories, Shionogi & Co, Ltd, Toyonaka, Osaka 561-0825, Japan. tomoyuki.honma@shionogi.co.jp
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Homma
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Hori
authors.forename: Merime
authors.initials: M
authors.lastname: Ohshiro
authors.forename: Hideki
authors.initials: H
authors.lastname: Maki
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Yamano
authors.forename: Jingoro
authors.initials: J
authors.lastname: Shimada
authors.forename: Shogo
authors.initials: S
authors.lastname: Kuwahara
mesh_terms: D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics* / Q000494:pharmacology*; D006193:Haemophilus influenzae / Q000187:drug effects*; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D013296:Streptococcus pneumoniae / Q000187:drug effects*
chemical_list: D000900:Anti-Bacterial Agents