Physiology-based Simulations of Amikacin Pharmacokinetics in Preterm Neonates
K. Claa▀en (1), S. Willmann (2), K. Thelen (3), K. Coboeken (2), K. Allegaert (4), J. Lippert (2)
(1) Radboud University Nijmegen, Organismale Dierfysiologie, 6525 AJ Nijmegen, Netherlands; (2) Bayer Technology Services GmbH, Systems Biology and Computational Solutions, Building E 41, 51368 Leverkusen, Germany; (3) Johann Wolfgang Goethe University Frankfurt, Institute of Pharmaceutical Technology, 60438 Frankfurt am Main, Germany; (4) University Hospitals Leuven, Department of Pediatrics, 3000 Leuven, Belgium
Objectives: This work aimed to extend the database of the physiology-based pharmacokinetic (PBPK) software PK-Sim« to enable simulations in preterm neonates down to 24 weeks of gestational age (GA). The implemented model accounts for both intrauterine development and the postnatal growth and maturation of anatomical and physiological parameters relevant for PBPK modeling.
Methods: Information about physiological parameters of neonates born between 24 and 40 weeks of gestation have been collected from the literature and implemented into the database of PK-Sim«. The aminoglycoside antibiotic amikacin was chosen as a model drug based on the availability of a previously established amikacin model for adults and therapeutic drug monitoring (TDM) data in preterms reported by Allegaert et al , . Plasma concentration time curves after a single intravenous dose of amikacin were simulated in virtual populations and compared to the experimental data obtained in neonates with a maximum postnatal age of 6 days.
Results: Simulation results of amikacin pharmacokinetics demonstrate a reasonable representation of TDM data in preterm neonates. Most data points fall within the 5th to 95th percentile of the simulated populations. Only a slight possible bias to lower predicted concentrations is observed.
Conclusions: A physiology-based model to simulate pharmacokinetics in preterm neonates has been developed and implemented in PK-Sim«. A comparison of simulated amikacin plasma concentrations with in vivo TDM data demonstrates the predictive capabilities of the preterm PBPK model.
 Allegaert, K., Cossey, V., Langhendries, J.P., Naulaers, G., Vanhole, C. et al. Effects of co-administration of ibuprofen-lysine on the pharmacokinetics of amikacin in preterm infants during the first days of life. Biol Neonate 86, 207-211 (2004).
 Allegaert, K., Scheers, I., Cossey, V. & Anderson, B.J. Covariates of amikacin clearance in neonates: the impact of postnatal age on predictability. Drug Metab Lett 2, 286-289 (2008).