Simultaneous pharmacokinetic modeling of gentamicin, tobramycin and vancomycin clearance from neonates to adults: towards a semi-physiological function for maturation in glomerular filtration.
OBJECTIVE
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 (ClGFR = Cldrug*(BW/4 kg)(BDE) with BDE = 2.23*BW(-0.065)). Population clearance values (Cldrug) for gentamicin, tobramycin and vancomycin were 0.21, 0.28 and 0.39 L/h for a full term neonate of 4 kg, 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.
Division of Pharmacology, LACDR, Leiden University, Leiden, The Netherlands.
Roosmarijn F W
RF
De Cock
Karel
K
Allegaert
Janneke M
JM
Brussee
Catherine M T
CM
Sherwin
Hussain
H
Mulla
Matthijs
M
de Hoog
Johannes N
JN
van den Anker
Meindert
M
Danhof
Catherijne A J
CA
Knibbe
D000293:Adolescent; D000328:Adult; D000375:Aging / Q000097:blood / Q000502:physiology*; D001835:Body Weight / Q000502:physiology; D002648:Child; D002675:Child, Preschool; D003404:Creatinine / Q000097:blood; D005839:Gentamicins / Q000493:pharmacokinetics*; D005919:Glomerular Filtration Rate / Q000502:physiology*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008657:Metabolic Clearance Rate; D008954:Models, Biological; D014031:Tobramycin / Q000493:pharmacokinetics*; D014640:Vancomycin / Q000493:pharmacokinetics*
D005839:Gentamicins; D014640:Vancomycin; D003404:Creatinine; D014031:Tobramycin