Vol.57 No.S-2 July 2009

Population pharmacokinetics and pharmacodynamics of 500 mg oral dose levofloxacin in respiratory tract infection patients

Yusuke Tanigawara¹⁾, Takako Shimizu²⁾ and Kyoichi Totsuka³⁾

¹⁾Department of Pharmacy, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo, Japan
²⁾R&D Division, Daiichi Sankyo Co., Ltd.
³⁾Department of Infectious Diseases, Tokyo Women's Medical University

Abstract

We analyzed levofloxacin(LVFX) population pharmacokinetics, and pharmacokinetics and pharmacodynamics(PK-PD) in Japanese subjects to evaluate a new 500 mg once-daily oral dosage regimen in Japan. Subjects were each orally administered once-daily LVFX 500 mg and plasma concentrations were measured; 1,362 concentrations of LVFX from 49 healthy or renally impaired subjects and 151 patients with respiratory tract infections were used for analysis. Population pharmacokinetic parameters were estimated using a nonlinear mixed effects model(NONMEM), applying a 2-compartment model with first-order absorption as a pharmacokinetic model. Covariates were tested for potential influence on LVFX pharmacokinetics. Significant influence was found from creatinine clearance on oral clearance (CL_t/F), body weight, and age on the apparent volume of distribution of the central compartment (V1/F), and food intake on absorption constant (k_a). Based on the population pharmacokinetic models and the distribution of minimum inhibitory concentration(MIC) for clinical isolates of Streptococcus pneumoniae, LVFX PK-PD parameters in patients administered 500 mg once-daily, 100 mg three-times daily, 200 mg twice or three-times daily were calculated by Monte-Carlo simulation. It showed that 93.5% of patients with 500 mg LVFX once daily reached C_max/MIC≥5, whereas 31.4% of those with 100 mg three times daily reached the target. The proportion of patients showing AUC_0-24h/MIC≥30 exceeded 95% under both dosing regimens. These results indicate that 500 mg LVFX once daily is to be effective comparable to 100 mg three times daily, and is to be more appropriate dose for respiratory tract infection patients to prevent the emergence of LVFX resistance.

Key word

levofloxacin, population pharmacokinetics, PK-PD

Received

December 15, 2008

Accepted

March 23, 2009

Jpn. J. Chemother. 57 (S-2): 47-54, 2009