Evaluation of a PBPK Model for Preterm Neonates by Predicting Paracetamol Pharmacokinetics
Karina Claassen (1), Stefan Willmann (2), Kirstin Thelen (2), Katrin Coboeken (2), Karel Allegaert (3), J÷rg Lippert (2)
(1) Jacobs University Bremen gGmbH, Bioinformatics, 28759 Bremen, Germany; (2) Bayer Technology Services GmbH, Systems Biology and Computational Solutions, Building 9115, 51368 Leverkusen, Germany; (3) University Hospitals Leuven, Department of Pediatrics, 3000 Leuven, Belgium
Objectives: This work aimed to validate the recently developed physiologically-based pharmacokinetic (PBPK) model for preterm neonates  by predicting the pharmacokinetics of paracetamol, a drug that undergoes hepatic clearance processes in addition to the renal excretion.
Methods: The recently presented model for preterm neonates has been extended by integrating information about hepatic enzyme ontogeny in fetuses and neonates. Propacetamol, a prodrug of paracetamol, was chosen as a model drug due to the multitude of processes involved in its elimination (renal excretion and hepatic metabolism via cytochrome P450 2E1, sulfotransferase 1A1, and UDP-glucuronosyltransferase 1A6) and the availability of therapeutic drug monitoring (TDM) data in 48 neonates reported by Allegaert et al. [2-3]. In this study, preterm neonates with a postmenstrual age of 27 to 43 weeks of gestation and a postnatal age of one to 76 days were given either single (n=30) or multiple doses (n=18) of propacetamol as an infusion over 15 minutes. Pharmacokinetics of paracetamol were predicted on the basis of a previously established paracetamol model for adults taking into account the anatomy and physiology of preterm neonates and postnatal changes such as body weight gain, changes in organ composition and blood flow changes.
Results: After integration of the developmental changes in preterm neonates that occur after birth and data on enzyme ontogeny, the extended PBPK model for preterm neonates could successfully predict individual paracetamol plasma concentrations for all postmenstrual and postnatal ages included in this study.
Conclusions: The good prediction of paracetamol elimination indicates a reasonable description of the ontogeny of the eliminating organs and the enzymes involved. In the future, this PBPK model might help to facilitate dose and dosing regimen decisions in preterm neonates.
 Claassen K, Willmann S, Thelen K, Coboeken K, Allegaert K, Lippert J. Physiology-based Simulations of Amikacin Pharmacokinetics in Preterm Neonates. Population Approach Group Europe; 2010; Berlin.
 Allegaert K, Anderson BJ, Naulaers G, de Hoon J, Verbesselt R, Debeer A, et al. Intravenous paracetamol (propacetamol) pharmacokinetics in term and preterm neonates. Eur J Clin Pharmacol. 2004 May;60(3):191-7.
 Allegaert K, Van der Marel CD, Debeer A, Pluim MA, Van Lingen RA, Vanhole C, et al. Pharmacokinetics of single dose intravenous propacetamol in neonates: effect of gestational age. Arch Dis Child Fetal Neonatal Ed. 2004 Jan;89(1):F25-8.