Development and application of neonatal physiology-based pharmacokinetic models of amikacin and fosfomycin to assess pharmacodynamic target attainment.
CPT Pharmacometrics Syst Pharmacol
; 13(3): 464-475, 2024 03.
Article
em En
| MEDLINE
| ID: mdl-38108548
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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Sepse Neonatal
/
Fosfomicina
Limite:
Humans
/
Newborn
Idioma:
En
Ano de publicação:
2024
Tipo de documento:
Article