Previous Article | Next Article 
Antimicrobial Agents and Chemotherapy, August 2009, p. 3462-3471, Vol. 53, No. 8
0066-4804/09/$08.00+0 doi:10.1128/AAC.00054-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.
New Semiphysiological Absorption Model To Assess the Pharmacodynamic Profile of Cefuroxime Axetil Using Nonparametric and Parametric Population Pharmacokinetics
,
J. B. Bulitta,1,
C. B. Landersdorfer,1,
M. Kinzig,1
U. Holzgrabe,2 and
F. Sorgel1,3*
Institute for Biomedical and Pharmaceutical Research (IBMP), Nürnberg-Heroldsberg, Germany,1 Institute of Pharmacy and Food Chemistry, University of Würzburg, Würzburg, Germany,2 Department of Pharmacology, University of Duisburg—Essen, Essen, Germany3
Received 14 January 2009/ Returned for modification 26 March 2009/ Accepted 3 June 2009
Cefuroxime axetil is widely used to treat respiratory tract infections. We are not aware of a population pharmacokinetic (PK) model for cefuroxime axetil. Our objectives were to develop a semiphysiological population PK model and evaluate the pharmacodynamic profile for cefuroxime axetil. Twenty-four healthy volunteers received 250 mg oral cefuroxime as a suspension after a standardized breakfast. Liquid chromatography-tandem mass spectrometry was used for drug analysis, NONMEM and S-ADAPT (results reported) were used for parametric population PK modeling, and NPAG was used for nonparametric population PK modeling. Monte Carlo simulations were used to predict the duration for which the non-protein-bound-plasma concentration was above the MIC (fT>MIC). A model with one disposition compartment, a saturable and time-dependent drug release from the stomach, and fast drug absorption from the intestine yielded precise (r > 0.992) and unbiased curve fits and an excellent predictive performance. The apparent clearance was 21.7 liters/h (19.8% coefficient of variation [CV]) and the volume of distribution 38.7 liters (18.3% CV). Robust (
90%) probabilities of target attainment (PTAs) were achieved by 250 mg cefuroxime given every 12 h (q12h) or q8h for MICs of 
0.375 mg/liter or 0.5 mg/liter, respectively, for the bacteriostasis target fT>MIC of 40% and for MICs of 0.094 mg/liter or 0.375 mg/liter, respectively, for the near-maximal-killing target fT>MIC of 65%. For the 40% fT>MIC target, the PTAs for 250 mg cefuroxime q12h were 97.8% for Streptococcus pyogenes and penicillin-susceptible Streptococcus pneumoniae. Cefuroxime at 250 mg q12h or q8h achieved PTAs below 73% or 92%, respectively, for Haemophilus influenzae, Moraxella catarrhalis, and penicillin-intermediate S. pneumoniae for susceptibility data from various countries. Depending on the MIC distribution, 250 mg oral cefuroxime q8h instead of q12h should be considered, especially for more-severe infections that require near-maximal killing by cefuroxime.
* Corresponding author. Mailing address: Institute for Biomedical and Pharmaceutical Research (IBMP), Paul-Ehrlich-Str. 19, D-90562 Nürnberg-Heroldsberg, Germany. Phone: 49-911-518290. Fax: 49-911-5182920. E-mail: ibmp{at}osn.de
Published ahead of print on 15 June 2009.
This article is dedicated to Ulrich Stephan, the cofounder of IBMP, who passed away on 6 February 2009. Without his inspiration and support, IBMP would not exist, and neither would the present research have been performed. We keep him in our hearts.
Present address: Ordway Research Institute, Albany, NY 12208.
Antimicrobial Agents and Chemotherapy, August 2009, p. 3462-3471, Vol. 53, No. 8
0066-4804/09/$08.00+0 doi:10.1128/AAC.00054-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.
Copyright © 2009 by the American Society for Microbiology. For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»