Journal
EXPERT OPINION ON DRUG METABOLISM & TOXICOLOGY
Volume 13, Issue 2, Pages 157-166Publisher
TAYLOR & FRANCIS LTD
DOI: 10.1080/17425255.2017.1234606
Keywords
Amikacin; antibiotics; implementation; nephrotoxicity; neonate; ototoxicity; prospective validation
Funding
- JoinEU-SEE
- Eraweb scholarship
- Fund for Scientific Research, Flanders [1800214N]
- agency for innovation by Science and Technology in Flanders (IWT) through the SAFEPEDRUG project [IWT/SBO 130033]
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Introduction: 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.
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