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- Title
Population pharmacokinetics and dosing optimization of azlocillin in neonates with early-onset sepsis: a real-world study.
- Authors
Wu, Yue-E; Wang, Tao; Yang, Hua-Liang; Tang, Bo-Hao; Kong, Li; Li, Xin; Gao, Qi; Li, Xue; Yao, Bu-Fan; Shi, Hai-Yan; Huang, Xin; Wang, Wen-Qi; Jacqz-Aigrain, Evelyne; Allegaert, Karel; van den Anker, John; Tian, Xiu-Ying; Zhao, Wei
- Abstract
<bold>Objectives: </bold>Nowadays, real-world data can be used to improve currently available dosing guidelines and to support regulatory approval of drugs for use in neonates by overcoming practical and ethical hurdles. This proof-of-concept study aimed to assess the population pharmacokinetics of azlocillin in neonates using real-world data, to make subsequent dose recommendations and to test these in neonates with early-onset sepsis (EOS).<bold>Methods: </bold>This prospective, open-label, investigator-initiated study of azlocillin in neonates with EOS was conducted using an adaptive two-step design. First, a maturational pharmacokinetic-pharmacodynamic model of azlocillin was developed, using an empirical dosing regimen combined with opportunistic samples resulting from waste material. Second, a Phase II clinical trial (ClinicalTrials.gov: NCT03932123) of this newly developed model-based dosing regimen of azlocillin was conducted to assure optimized target attainment [free drug concentration above MIC during 70% of the dosing interval ('70% fT>MIC')] and to investigate the tolerance and safety in neonates.<bold>Results: </bold>A one-compartment model with first-order elimination, using 167 azlocillin concentrations from 95 neonates (31.7-41.6 weeks postmenstrual age), incorporating current weight and renal maturation, fitted the data best. For the second step, 45 neonates (30.3-41.3 weeks postmenstrual age) were subsequently included to investigate target attainment, tolerance and safety of the pharmacokinetic-pharmacodynamic model-based dose regimen (100 mg/kg q8h). Forty-three (95.6%) neonates reached their pharmacokinetic target and only two neonates experienced adverse events (feeding intolerance and abnormal liver function), possibly related to azlocillin.<bold>Conclusions: </bold>Target attainment, tolerance and safety of azlocillin was shown in neonates with EOS using a pharmacokinetic-pharmacodynamic model developed with real-world data.
- Subjects
ANTIBIOTICS; RESEARCH; CLINICAL trials; RESEARCH methodology; MEDICAL cooperation; EVALUATION research; SEPSIS; COMPARATIVE studies; AMPICILLIN; MICROBIAL sensitivity tests; LONGITUDINAL method
- Publication
Journal of Antimicrobial Chemotherapy (JAC), 2021, Vol 76, Issue 3, p699
- ISSN
0305-7453
- Publication type
journal article
- DOI
10.1093/jac/dkaa468