Vol.59 No.S-1 May 2011
Population pharmacokinetics and pharmacodynamics of levofloxacin following intravenous infusion for respiratory tract infection
1)Department of Clinical Pharmacokinetics and Pharmacodynamics, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo, Japan
2)R&D Division, Daiichi Sankyo Company, Limited
3)Department of Infectious Diseases, Tokyo Women's Medical University
Abstract
Our population pharmacokinetic analysis of levofloxacin (LVFX) used 1,381 plasma drug concentration data from 64 healthy Japanese adult volunteers (including elderly and female subjects) and 195 subjects with respiratory tract infection administered intravenous infusions of 500 mg of LVFX once daily. Population pharmacokinetic parameters were estimated using a nonlinear mixed-effect model (NONMEM) applying a 2-compartment model as a pharmacokinetic structure model. Creatinine clearance was related to LVFX total body clearance, and body weight was related to distribution volume in the central and peripheral compartments. In plasma LVFX concentration simulation under using final estimates of population pharmacokinetic parameters, impaired renal function was associated with accumulated plasma concentration in repeated dosing of 500 mg once daily, but the application of a dose adjustment algorithm similar to that for oral LVFX prevented plasma concentration increase on days 1-7. Prediction of LVFX PK-PD parameters in the population with respiratory tract infection by Monte Carlo simulation showed that target AUC0-24h/MIC≥30 considered necessary to eradicate Streptococcus pneumoniae and target Cmax/MIC≥5 considered necessary to prevent the LVFX resistance were achieved in almost 100% at a dose of 500 mg once daily with MIC of 1 μg/mL or less. Oral LVFX bioavailability was estimated at 98% from population pharmacokinetic parameters for intravenous and oral administration. Systemic exposure to LVFX after intravenous administration resembles that after oral administration of the same dose. A dose of 500 mg once daily is thus appropriate in pharmacokinetics-pharmacodynamics.
Key word
levofloxacin, population pharmacokinetics, PK-PD
Received
December 10, 2010
Accepted
February 1, 2011
Jpn. J. Chemother. 59 (S-1): 55-64, 2011
