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3223625 
Journal Article 
Simultaneous Pharmacokinetic Modeling of Gentamicin, Tobramycin and Vancomycin Clearance from Neonates to Adults: Towards a Semi-physiological Function for Maturation in Glomerular Filtration 
De Cock, RFW; Allegaert, K; Brussee, JM; Sherwin, CMT; Mulla, H; de Hoog, M; van Den Anker, JN; Danhof, M; Knibbe, CAJ 
2014 
1 
Pharmaceutical Research
ISSN: 0724-8741
EISSN: 1573-904X 
31 
10 
2643-2654 
WOS:000343889300007 
Purpose Since glomerular filtration rate (GFR) is responsible for the elimination of a large number of water-soluble drugs, the aim of this study was to develop a semi-physiological function for GFR maturation from neonates to adults.



Methods In the pharmacokinetic analysis (NONMEM VI) based on data of gentamicin, tobramycin and vancomycin collected in 1,760 patients (age 1 day-18 years, bodyweight 415 g-85 kg), a distinction was made between drug-specific and system-specific information. Since the maturational model for clearance is considered to contain system-specific information on the developmental changes in GFR, one GFR maturational function was derived for all three drugs.



Results Simultaneous analysis of these three drugs showed that maturation of GFR mediated clearance from preterm neonates to adults was best described by a bodyweight-dependent exponent (BDE) function with an exponent varying from 1.4 in neonates to 1.0 in adults (Cl-GFR= Cl-drug*(BW/4 kg)(BDE) with BDE = 2.23*BW-0.065). Population clearance values (Cl-drug) for gentamicin, tobramycin and vancomycin were 0.21, 0.28 and 0.39 L/h for a full term neonate of 4 kg, respectively.



Discussion Based on an integrated analysis of gentamicin, tobramycin and vancomycin, a semi-physiological function for GFR mediated clearance was derived that can potentially be used to establish evidence based dosing regimens of renally excreted drugs in children. 
antibiotics; developmental changes; glomerular filtration; pediatric age range