Towards Rational Dosing Algorithms for Vancomycin in Neonates and Infants Based on Population Pharmacokinetic Modeling.

Because of the recent awareness that vancomycin doses should aim to meet a target area under the concentration-time curve (AUC) instead of trough concentrations, more aggressive dosing regimens are warranted also in the pediatric population. In this study, both neonatal and pediatric pharmacokinetic models for vancomycin were externally evaluated and subsequently used to derive model-based dosing algorithms for neonates, infants, and children. For the external validation, predictions from previously published pharmacokinetic models were compared to new data.

Novel model-based dosing guidelines for gentamicin and tobramycin in preterm and term neonates.

Objectives: In the heterogeneous group of preterm and term neonates, gentamicin and tobramycin are mainly dosed according to empirical guidelines, after which therapeutic drug monitoring and subsequent dose adaptation are applied. In view of the variety of neonatal guidelines available, the purpose of this study was to evaluate target concentration attainment of these guidelines, and to propose a new model-based dosing guideline for these drugs in neonates.

Methods: Demographic characteristics of 1854 neonates (birth weight 390-5200 g, post-natal age 0-27 days) were extracted from earlier studies and sampled to obtain a test dataset of 5000 virtual patients.

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

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.

Low but inducible contribution of renal elimination to clearance of propylene glycol in preterm and term neonates.

Background: Despite limited information being available on the pharmacokinetics of excipients, propylene glycol (PG) is often used as an excipient in both adults and children. The aim of this study is to characterize the renal and hepatic elimination of PG in preterm and term neonates.

Methods: The pharmacokinetic analysis of PG was performed in NONMEM 6.

A neonatal amikacin covariate model can be used to predict ontogeny of other drugs eliminated through glomerular filtration in neonates.

Purpose: Recently, a covariate model characterizing developmental changes in clearance of amikacin in neonates has been developed using birth bodyweight and postnatal age. The aim of this study was to evaluate whether this covariate model can be used to predict maturation in clearance of other renally excreted drugs.

Methods: Five different neonatal datasets were available on netilmicin, vancomycin, tobramycin and gentamicin.

Is indirect hyperbilirubinemia a useful biomarker of reduced propofol clearance in neonates?

Aim: Large interindividual variability in neonatal propofol clearance is documented which, in part, can be explained by postmenstrual age (PMA) and postnatal age (PNA). We aimed to document whether indirect bilirubin, instead of or in addition to PNA, could improve predictability of propofol clearance and serve as a useful biomarker of reduced propofol clearance in neonates.

Methods: Indirect serum bilirubin was introduced as a dichotomous or continuous variable (both age-normalized) in a previously developed three-compartment pharmacokinetic model, based on 235 concentration-time points obtained in 25 neonates after single bolus administration of propofol.

Developmental pharmacokinetics of propylene glycol in preterm and term neonates.

Aim: Propylene glycol (PG) is often applied as an excipient in drug formulations. As these formulations may also be used in neonates, the aim of this study was to characterize the pharmacokinetics of propylene glycol, co-administered intravenously with paracetamol (800 mg PG/1000 mg paracetamol) or phenobarbital (700 mg PG/200 mg phenobarbital) in preterm and term neonates.

Methods: A population pharmacokinetic analysis was performed based on 372 PG plasma concentrations from 62 (pre)term neonates (birth weight (bBW) 630-3980 g, postnatal age (PNA) 1-30 days) using NONMEM 6.

Maturation of the glomerular filtration rate in neonates, as reflected by amikacin clearance.

Background And Objectives: During the newborn period and early infancy, renal function matures, resulting in changes in the glomerular filtration rate (GFR). This study was performed to quantify developmental changes in the GFR in (pre)term neonates by use of amikacin clearance as proof of concept. The model was used to derive a rational dosing regimen in comparison with currently used dosing regimens for amikacin.

The role of population PK-PD modelling in paediatric clinical research.

Children differ from adults in their response to drugs. While this may be the result of changes in dose exposure (pharmacokinetics [PK]) and/or exposure response (pharmacodynamics [PD]) relationships, the magnitude of these changes may not be solely reflected by differences in body weight. As a consequence, dosing recommendations empirically derived from adults dosing regimens using linear extrapolations based on body weight, can result in therapeutic failure, occurrence of adverse effect or even fatalities.