Pharmacodynamic target assessment and prediction of clinically effective dosing regimen of TP0586532, a novel non-hydroxamate LpxC inhibitor, using a murine lung infection model

Kiyoko Fujita; Iichiro Takata; Ippei Yoshida; Yusuke Honma; Hirotoshi Okumura; Katsumasa Otake; Hajime Takashima; Hiroyuki Sugiyama

doi:10.1016/j.jiac.2022.01.004

Pharmacodynamic target assessment and prediction of clinically effective dosing regimen of TP0586532, a novel non-hydroxamate LpxC inhibitor, using a murine lung infection model

J Infect Chemother. 2022 May;28(5):635-642. doi: 10.1016/j.jiac.2022.01.004. Epub 2022 Feb 5.

Authors

Kiyoko Fujita¹, Iichiro Takata¹, Ippei Yoshida¹, Yusuke Honma¹, Hirotoshi Okumura¹, Katsumasa Otake¹, Hajime Takashima¹, Hiroyuki Sugiyama²

Affiliations

¹ Taisho Pharmaceutical Co., Ltd., 1-403, Yoshino-cho, Kita-ku, Saitama, 331-9530, Japan.
² Taisho Pharmaceutical Co., Ltd., 1-403, Yoshino-cho, Kita-ku, Saitama, 331-9530, Japan; Taisho Pharmaceutical Co., Ltd., 3-24-1, Takada, Toshima-ku, Tokyo, 170-8633, Japan. Electronic address: hiro-sugiyama@taisho.co.jp.

PMID: 35131156
DOI: 10.1016/j.jiac.2022.01.004

Abstract

Introduction: TP0586532 is a novel non-hydroxamate UDP-3-O-acyl-N-acetylglucosamine deacetylase (LpxC) inhibitor. Pharmacokinetic/pharmacodynamic (PK/PD) indices and magnitude of index that correlated with the efficacy of TP0586532 were determined and used to estimate the clinically effective doses of TP0586532.

Methods: Dose-fractionation studies were conducted using a murine neutropenic lung infection model caused by carbapenem-resistant Enterobacteriaceae. The relationships between the efficacy and the PK/PD index (the maximum unbound plasma concentration divided by the MIC [fC_max/MIC], the area under the unbound plasma concentration-time curve from 0 to 24 h divided by the MIC, and the cumulative percentage of a 24-h period that the unbound plasma concentration exceeds the MIC) were determined using an inhibitory sigmoid maximum-effect model. In addition, the magnitudes of fC_max/MIC were evaluated using the dose-response relationships for each of the seven carbapenem-resistant strains of Enterobacteriaceae. Furthermore, the clinically effective doses of TP0586532 were estimated using the predicted human PK parameters, the geometric mean of fC_max/MIC, and the MIC₉₀ for carbapenem-resistant Klebsiella pneumoniae.

Results: The PK/PD index that best correlated with the efficacy was the fC_max/MIC. The geometric means of the fC_max/MIC associated with the net stasis and 1-log reduction endpoints were 2.30 and 3.28, respectively. The clinically effective doses of TP0586532 were estimated to be 1.24-2.74 g/day.

Conclusion: These results indicate the potential for TP0586532 to have clinical efficacy at reasonable doses against infections caused by carbapenem-resistant Enterobacteriaceae. This study provided helpful information for a clinically effective dosing regimen of TP0586532.

Keywords: Carbapenem-resistant Enterobacteriaceae; LpxC inhibitor; PK/PD study; TP0586532.

MeSH terms

Animals
Anti-Bacterial Agents* / pharmacology
Anti-Bacterial Agents* / therapeutic use
Enterobacteriaceae
Humans
Klebsiella pneumoniae*
Lung
Mice
Microbial Sensitivity Tests

Substances

Anti-Bacterial Agents