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Antimicrobial Agents and Chemotherapy, April 2004, p. 1159-1167, Vol. 48, No. 4
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.4.1159-1167.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Population Pharmacokinetics of Arbekacin, Vancomycin, and Panipenem in Neonates

Department of Pharmacy,¹ Division of Neonatology, Kitasato University Hospital,³ Division of Infectious Disease, Kitasato University School of Medicine, 1-15-1 Kitasato, Sagamihara-shi, Kanagawa 228-8555,² Laboratory of Analytical Chemistry, School of Parmaceutical Sciences, Kitasato University, 108-8641 Shirogane, Minatoku, Tokyo, Japan⁴

Received 27 January 2003/ Returned for modification 29 August 2003/ Accepted 20 December 2003

Immature renal function in neonates requires antibiotic dosage adjustment. Population pharmacokinetic studies were performed to determine the optimal dosage regimens for three types of antibiotics: an aminoglycoside, arbekacin; a glycopeptide, vancomycin; and a carbapenem, panipenem. Eighty-three neonates received arbekacin (n = 41), vancomycin (n = 19), or panipenem (n = 23). The postconceptional ages (PCAs) were 24.1 to 48.4 weeks, and the body weights (BWs) ranged from 458 to 5,200 g. A one-compartment open model with first-order elimination was applied and evaluated with a nonlinear mixed-effect model for population pharmacokinetic analysis. In the fitting process, the fixed effects significantly related to clearance (CL) were PCA, postnatal age, gestational age, BW, and serum creatinine level; and the fixed effect significantly related to the volume of distribution (V) was BW. The final formulas for the population pharmacokinetic parameters are as follows: CL_arbekacin = 0.0238 x BW/serum creatinine level for PCAs of <33 weeks and CL_arbekacin = 0.0367 x BW/serum creatinine level for PCAs of 33 weeks, V_arbekacin = 0.54 liters/kg, CL_vancomycin = 0.0250 x BW/serum creatinine level for PCAs of <34 weeks and CL_vancomycin = 0.0323 x BW/serum creatinine level for PCAs of 34 weeks, V_vancomycin = 0.66 liters/kg, CL_panipenem = 0.0832 for PCAs of <33 weeks and CL_panipenem = 0.179 x BW for PCAs of 33 weeks, and V_panipenem = 0.53 liters/kg. When the CL of each drug was evaluated by the nonlinear mixed-effect model, we found that the mean CL for subjects with PCAs of <33 to 34 weeks was significantly smaller than those with PCAs of 33 to 34 weeks, and CL showed an exponential increase with PCA. Many antibiotics are excreted by glomerular filtration, and maturation of glomerular filtration is the most important factor for estimation of antibiotic clearance. Clinicians should consider PCA, serum creatinine level, BW, and chemical features when determining the initial antibiotic dosing regimen for neonates.

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