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

ABSTRACT

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.

KEYWORDS:

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

Article highlights

• We describe our approach to develop an amikacin dosing regimen in neonates. This has been performed using pharmacometrics based on therapeutic drug monitoring (TDM) observations collected during routine clinical care. The final model considers current weight, postnatal age, perinatal asphyxia and ibuprofen exposure.

• This dosing regimen was subsequently validated (target concentrations reached as surrogate marker) in a prospective study, illustrating feasibility and relevance (further adaptations in specific subgroups). A similar approach should be considered for other drugs in neonates. Moreover, the same approach can be used to explore the impact of new covariates (e.g. perinatal asphyxia and whole body hypothermia).

• Using a pragmatic sampling approach, data on deep compartment amikacin disposition (cerebrospinal fluid, bronchial epithelial lining fluid) were collected.

• New observations on mechanisms and risk factors of developmental oto- and nephrotoxicity have been reported. Cellular aminoglycoside accumulation may occur through a megalin-independent cation influx. This influx may be enhanced by noise (mechano-electronic transduction ion channels) or loop diuretics (cation channels). Risk factors need to focus on synergism and pharmacogenetics.

• To further improve the safety of aminoglycosides - including amikacin - the impact of pharmacogenetics, co-medication or disease characteristics, biomarkers, and renal long term outcome should be further explored in both animal experimental settings and in rich datasets from cohorts of former human neonates (e.g. Mitogent study, SAFEPEDRUG study), using the earlier validated dosing regimens.

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Declaration of interest

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

A Kulo was supported by a JoinEU-SEE (2010–2012) and Eraweb (2015/16) scholarship. K Allegaert was supported by the Fund for Scientific Research, Flanders (fundamental clinical investigatorship 1800214N). The research activities are further facilitated by the agency for innovation by Science and Technology in Flanders (IWT) through the SAFEPEDRUG project (IWT/SBO 130033).