Simultaneous pharmacokinetic modeling of gentamicin, tobramycin and vancomycin clearance from neonates to adults: towards a semi-physiological function for maturation in glomerular filtration

Abstract

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 (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.

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.

Fig. 1

Individual post hoc (grey) and population predicted (black) clearance values (L/h) versus the most predictive covariate bodyweight for the three different drugs using the final system-specific pharmacology model (a, b, c).

Fig. 2

Observed versus population predicted concentrations of the final system-specific pharmacology model for gentamicin, tobramycin and vancomycin, split by four age categories.

Fig. 3

Individual (grey) and population predicted (black) clearance values for gentamicin, tobramycin and vancomycin versus bodyweight (kg) for the final system-specific pharmacology model.

Fig. 4

Population predicted clearance values versus bodyweight for the final system-specific pharmacology model (grey) and independent reference models (black) for the three different drugs.

Fig. 5

NPDE results of the final system-specific pharmacology model for the three different drugs. Left panel: Histogram of the NPDE distribution with the solid line representing a normal distribution, middle panel: NPDE versus time, right panel: NPDE versus predicted concentrations.

Fig. 6

The relationship between the allometric exponent in the final system-specific pharmacology model and bodyweight (kg) in the bodyweight-dependent exponent model (Eq. 9).