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Expert Opin Drug Metab Toxicol. 2017 Feb;13(2):157-166. doi: 10.1080/17425255.2017.1234606. Epub 2016 Sep 21.

The amikacin research program: a stepwise approach to validate dosing regimens in neonates.

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a Neonatal Intensive Care Unit , VU Medical Center , Amsterdam , The Netherlands.
b Neonatal Intensive Care Unit , University Hospitals Leuven , Leuven , Belgium.
c Institute of Pharmacology, Clinical Pharmacology and Toxicology, Faculty of Medicine , University of Sarajevo , Sarajevo , Bosnia Herzegovina.
d Intensive Care and Department of Surgery , Erasmus MC Sophia Children's Hospital , Rotterdam , The Netherlands.
e Department of Paediatric Pharmacology , University Children's Hospital Basel , Basel , Switzerland.
f Division of Pediatric Clinical Pharmacology , Children's National Medical Center , Washington , DC , USA.
g Departments of Pediatrics, Integrative Systems Biology, Pharmacology & Physiology , George Washington University School of Medicine and Health Sciences , Washington , DC , USA.
h Department of Development and Regeneration , KU Leuven , Leuven , Belgium.


For safe and effective use of antibacterial agents in neonates, specific knowledge on the pharmacokinetics (PK) and its covariates is needed. This necessitates a stepwise approach, including prospective validation. Areas covered: We describe our approach throughout almost two decades to improve amikacin exposure in neonates. A dosing regimen has been developed and validated using pharmacometrics, considering current weight, postnatal age, perinatal asphyxia, and ibuprofen use. This regimen has been developed based on clinical and therapeutic drug monitoring (TDM) data collected during routine care, and subsequently underwent prospective validation. A similar approach has been scheduled to quantify the impact of hypothermia. Besides plasma observations, datasets on deep compartment PK were also collected. Finally, the available literature on developmental toxicology (hearing, renal) of amikacin is summarized. Expert opinion: The amikacin model reflects a semi-physiological function for glomerular filtration. Consequently, this model can be used to develop dosing regimens for other aminoglycosides or to validate physiology-based pharmacokinetic models. Future studies should explore safety with incorporation of covariates like pharmacogenetics, biomarkers, and long-term outcomes. This includes a search for mechanisms of developmental toxicity. Following knowledge generation and grading the level of evidence in support of data, dissemination and implementation initiatives are needed.


Amikacin; antibiotics; implementation; neonate; nephrotoxicity; ototoxicity; prospective validation

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