Vol.69 No.4 July 2021

Population pharmacokinetics and pharmacodynamics of intravenous lascufloxacin in patients with respiratory tract 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 was constructed and pharmacokinetics/pharmacodynamics (PK/PD) analysis was performed to evaluate the adequacy of the dosage of intravenous lascufloxacin (LSFX) in patients with respiratory tract infections.
For the PPK analysis, the PPK model was reconstructed by adding the results of the Phase III clinical study of intravenous LSFX to the simultaneous analysis model of oral administration and intravenous infusions constructed for PPK analysis of Lasvic^Ⓡ Tablets 75 mg. The time-concentration profile of LSFX is described by a one-compartment model with first-order absorption considering nonlinear elimination by mechanism-based inactivation. Body weight was identified as the covariate for systemic clearance and volume of distribution with the largest effect on the LSFX exposure. The basic model structure, parameter values, and types of covariates that affected the parameters of the model were same as those in the PPK model of Lasvic^Ⓡ Tablets 75 mg.
For the PK/PD analysis, the efficacy target value of intravenous LSFX was estimated at AUC_0-24/MIC >15 (free AUC_0-24/MIC >3.9), based on the calculated AUC_0-24/MIC value and the microbiological effect in the patients in whom the causative organism was isolated. The probability of target attainment calculated by the Monte Carlo simulation was 97.3% on the first day of infusion and 96.9% on the seventh day of infusion. In patients from whom the applicable bacteria were isolated, the percentage of causative organisms for which C_max/MIC >8 achieved was 87.8%, which is the index of suppression of resistance. The probability of target attainment of C_max/MIC >8 calculated by the Monte Carlo simulation was 87.8% or higher throughout the treatment period.
The results of the PK/PD analysis supported the adequacy of the dosage of intravenous LSFX 150 mg (300 mg on the first day) administered once daily in patients with respiratory tract infections.

Key word

lascufloxacin, population pharmacokinetics, PK/PD

Received

January 29, 2021

Accepted

March 30, 2021

Jpn. J. Chemother. 69 (4): 305-317, 2021