Development and application of neonatal physiology-based pharmacokinetic models of amikacin and fosfomycin to assess pharmacodynamic target attainment.

Darlow, Christopher A ORCID: 0000-0002-5400-3413, Parrott, Neil, Peck, Richard W ORCID: 0000-0003-1018-9655 and Hope, William ORCID: 0000-0001-6187-878X (2023) Development and application of neonatal physiology-based pharmacokinetic models of amikacin and fosfomycin to assess pharmacodynamic target attainment. CPT: pharmacometrics & systems pharmacology, 13 (3). pp. 464-475.

Access the full-text of this item by clicking on the Open Access link.

Official URL: http://dx.doi.org/10.1002/psp4.13097

Abstract

Antimicrobial resistance increasingly complicates neonatal sepsis in a global context. Fosfomycin and amikacin are two agents being tested in an ongoing multicenter neonatal sepsis trial. Although neonatal pharmacokinetics (PKs) have been described for these drugs, the physiological variability within neonatal populations makes population PKs in this group uncertain. Physiologically-based pharmacokinetic (PBPK) models were developed in Simcyp for fosfomycin and amikacin sequentially for adult, pediatric, and neonatal populations, with visual and quantitative validation compared to observed data at each stage. Simulations were performed using the final validated neonatal models to determine drug exposures for each drug across a demographic range, with probability of target attainment (PTA) assessments. Successfully validated neonatal PBPK models were developed for both fosfomycin and amikacin. PTA analysis demonstrated high probability of target attainment for amikacin 15 mg/kg i.v. q24h and fosfomycin 100 mg/kg (in neonates aged 0-7 days) or 150 mg/kg (in neonates aged 7-28 days) i.v. q12h for Enterobacterales with fosfomycin and amikacin minimum inhibitory concentrations at the adult breakpoints. Repeat analysis in premature populations demonstrated the same result. PTA analysis for a proposed combination fosfomycin-amikacin target was also performed. The simulated regimens, tested in a neonatal sepsis trial, are likely to be adequate for neonates across different postnatal ages and gestational age. This work demonstrates a template for determining target attainment for antimicrobials (alone or in combination) in special populations without sufficient available PK data to otherwise assess with traditional pharmacometric methods.

Item Type:	Article
Uncontrolled Keywords:	Humans, Fosfomycin, Amikacin, Anti-Bacterial Agents, Microbial Sensitivity Tests, Infant, Newborn, Clinical Trials as Topic, Multicenter Studies as Topic, Neonatal Sepsis
Divisions:	Faculty of Health and Life Sciences Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology
Depositing User:	Symplectic Admin
Date Deposited:	24 Jan 2024 11:03
Last Modified:	02 Apr 2024 09:31
DOI:	10.1002/psp4.13097
Open Access URL:	https://doi.org/10.1002/psp4.13097
Related URLs:	Author Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3177977