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Abstract

Vol.68 No.S-1 November 2020

Population pharmacokinetics and pharmacodynamics of oral lascufloxacin in patients with respiratory tract and otorhinolaryngological infections

Kyoichi Totsuka1), Junichi Takano2) and Yuichi Masuda3)

1)Department of Internal Medicine, Kita-tama Hospital, 4-1-1 Chofugaoka, Chofu, Tokyo, Japan
2)Watarase Research Center, Kyorin pharmaceutical Co., LTD.
3)Clinical Development Center, Kyorin pharmaceutical Co., LTD.

Abstract

A population pharmacokinetics (PPK) model of lascufloxacin (LSFX) in patients with respiratory tract and otorhinolaryngological infections was constructed to clarify the covariates for pharmacokinetics. The time-concentration profile of LSFX was described by a one-compartment model with first-order absorption considering nonlinear elimination by mechanism-based inactivation. Body weight was identified as a covariate for systemic clearance and volume of distribution with the largest effect on the LSFX exposure.
Pharmacokinetics/pharmacodynamics (PK/PD) analysis was performed to evaluate the validity of the dosing regimen of oral LSFX of 75 mg once daily in patients with respiratory tract infections. Individual pharmacokinetic parameters of the patients were estimated from the PPK model, and the PK/PD parameters were calculated using the MIC for the pathogen isolated from each patient. The estimated target value of clinical efficacy was AUC0-24/MIC>15 (free AUC0-24/MIC>3.9), based on the relationship between the PK/PD parameters of the patients and the bacteriological responses. Probability of target attainment was calculated by Monte Carlo Simulation to evaluate the clinical efficacy and prevention of resistance to LSFX. It showed that 92.3% of patients achieved AUC0-24/MIC>15 as the index of clinical efficacy, 98.3% of patients achieved Cmax/MIC>5 for clinical isolates of Streptococcus pneumoniae, and 98.6% of patients achieved trough concentration > mutant prevention concentration (Ctrough>MPC) for S. pneumoniae as the indices of resistance selection.
The results of the PK/PD analysis supported the validity of the dosing regimen of oral LSFX of 75 mg once daily.

Key word

lascufloxacin, population pharmacokinetics, PK/PD

Received

October 30, 2019

Accepted

May 8, 2020

Jpn. J. Chemother. 68 (S-1): 96-108, 2020