Population Pharmacokinetics And Dosing Optimization Of Azlocillin In Neonates With Early-Onset Sepsis: A Real-World Study

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 aziocillin 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 aziocillin in neonates with EOS was conducted using an adaptive two-step design. First, a maturational pharmacokinetic-pharmacodynamic model of aziocillin 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 aziocillin 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 aziocillin 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 aziocillin.Conclusions: Target attainment, tolerance and safety of aziocillin was shown in neonates with EOS using a pharmacokinetic-pharmacodynamic model developed with real-world data.