Simultaneous Pharmacokinetic Modeling of Gentamicin, Tobramycin and Vancomycin Clearance From Neonates to Adults: Towards a Semi-Physiological Function for Maturation in Glomerular Filtration

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Objectives: Since glomerular filtration rate (GFR) is responsible for the elimination of a large number of water-soluble drugs [1], 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 1760 patients (age 1 day-18 years, bodyweight 415g-85kg), 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 [2], 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 (ClGFR= Cldrug*(BW/4kg)BDE with BDE=2.23*BW-0.065). Population clearance values (Cldrug) for gentamicin, tobramycin and vancomycin were 0.21L/h, 0.28L/h and 0.39L/h for a full term neonate of 4kg, respectively.

Conclusions: 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.