Development and application of neonatal physiology-based pharmacokinetic models of amikacin and fosfomycin to assess pharmacodynamic target attainment.
Christopher A DarlowNeil John ParrottRichard Wilson PeckWilliam HopePublished in: CPT: pharmacometrics & systems pharmacology (2023)
Antimicrobial resistance increasingly complicates neonatal sepsis in a global context. Fosfomycin and amikacin are two agents being tested in an ongoing multi-centre neonatal sepsis trial. Although neonatal pharmacokinetics have been described for these drugs, the physiological variability within neonatal populations makes population pharmacokinetics in this group uncertain. Physiology-based pharmacokinetic (PBPK) models were developed in Simcyp for fosfomycin and amikacin sequentially for adult, paediatric 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 15mg/kg IV q24h and fosfomycin 100mg/kg (in neonates aged 0-7 days) or 150mg/kg (in neonates aged 7-28 days) IV q12h for Enterobacterales with fosfomycin and amikacin MICs 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 (NeoSep), are likely to be adequate for neonates across different post-natal ages and gestational age. This work demonstrates a template for determining target attainment for antimicrobials (alone or in combination) in special populations without limited available pharmacokinetic data to assess with traditional pharmacometric methods.
Keyphrases
- urinary tract infection
- gram negative
- antimicrobial resistance
- acute kidney injury
- emergency department
- gestational age
- clinical trial
- randomized controlled trial
- body mass index
- study protocol
- mass spectrometry
- high resolution
- preterm infants
- low birth weight
- south africa
- machine learning
- birth weight
- artificial intelligence
- phase ii
- preterm birth
- data analysis
- adverse drug