Population Pharmacokinetic Comparison and Pharmacodynamic ...

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Jul 7, 2009 - Allometric scaling by fat-free mass reduced the between-subject variability by 32% for ... Mailing address: IBMP Institute for Bio- medical and ...
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Mar. 2010, p. 1275–1282 0066-4804/10/$12.00 doi:10.1128/AAC.00936-09 Copyright © 2010, American Society for Microbiology. All Rights Reserved.

Vol. 54, No. 3

Population Pharmacokinetic Comparison and Pharmacodynamic Breakpoints of Ceftazidime in Cystic Fibrosis Patients and Healthy Volunteers䌤 J. B. Bulitta,1† C. B. Landersdorfer,1† S. J. Hu ¨ttner,1 G. L. Drusano,2 1 3 1,4 M. Kinzig, U. Holzgrabe, U. Stephan, ‡ and F. So ¨rgel1,5* IBMP Institute for Biomedical and Pharmaceutical Research, Nu ¨rnberg-Heroldsberg, Germany1; Ordway Research Institute, Albany, 2 New York ; Institute of Pharmacy and Food Chemistry, University of Wu ¨rzburg, Wu ¨rzburg, Germany3; Department of Pediatrics, University of Duisburg-Essen, Essen, Germany4; and Department of Pharmacology, University of Duisburg-Essen, Essen, Germany5 Received 7 July 2009/Returned for modification 29 September 2009/Accepted 29 December 2009

Despite the promising activity of ceftazidime against Pseudomonas aeruginosa and Burkholderia cepacia, there has not yet been a study that directly compared the pharmacokinetics (PK) of ceftazidime in cystic fibrosis (CF) patients and healthy volunteers by population PK methodology. We assessed the population PK and PK/pharmacodynamic (PD) breakpoints of ceftazidime in CF patients and healthy volunteers. Eight CF patients (total body weight [WT] [average ⴞ standard deviation] ⴝ 42.9 ⴞ 18.4 kg) and seven healthy volunteers (WT ⴝ 66.2 ⴞ 4.9 kg) received 2 g ceftazidime as a 5-min intravenous infusion. High-performance liquid chromatography (HPLC) was used for drug analysis, and NONMEM (results reported), S-ADAPT, and NPAG were used for parametric and nonparametric population PK modeling. We considered linear and allometric body size models to scale clearance and volume of distribution. Monte Carlo simulations were based on a target time of non-protein-bound plasma concentration of ceftazidime above MIC of >65%, which represents near-maximal killing. Unscaled total clearance was 19% lower in CF patients, and volume of distribution was 36% lower. Total clearance was 7.82 liters/h for CF patients and 6.68 liters/h for healthy volunteers with 53 kg fat-free mass. Allometric scaling by fat-free mass reduced the between-subject variability by 32% for clearance and by 18 to 26% for volume of both peripheral compartments compared to linear scaling by WT. A 30-min ceftazidime infusion of 2 g/70 kg WT every 8 h (q8h) achieved robust (>90%) probabilities of target attainment (PTAs) for MICs of