Population pharmacokinetics and dosing optimization of azlocillin in neonates with early-onset sepsis: a real-world study

YE Wu, T Wang, HL Yang, BH Tang, L Kong, X Li, Q Gao, XI Li, BF Yao, HY Shi, X Huang, WQ Wang, E Jacqz-Aigrain, Karel Allegaert, J Anker, XY Tian, W Zhao

Research output: Contribution to journalArticleAcademicpeer-review

8 Citations (Scopus)

Abstract

Objectives: 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). Methods: 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. Results: 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. Conclusions: Target attainment, tolerance and safety of azlocillin was shown in neonates with EOS using a pharmacokinetic-pharmacodynamic model developed with real-world data.

Original languageEnglish
Pages (from-to)699-709
Number of pages11
JournalJournal of Antimicrobial Chemotherapy
Volume76
Issue number3
DOIs
Publication statusPublished - Mar 2021

Bibliographical note

Publisher Copyright:
© 2021 The Author(s). Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved.

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