Determination of vancomycin exposure target and individualised dosing recommendations for neonates: model-informed precision dosing

Abstract

IntroductionFew studies incorporating population pharmacokinetic/pharmacodynamic (Pop-PK/PD) modelling have been conducted to quantify the exposure target of vancomycin in neonates. A retrospective observational cohort study was undertaken in neonates to determine this target and dosing recommendations (chictr.org.cn, ChiCTR1900027919). MethodsA Pop-PK model was developed to estimate PK parameters. Causalities between acute kidney injury (AKI) occurrence and vancomycin use were verified using Naranjo criteria. Thresholds of vancomycin exposure in predicting AKI or efficacy were identified via classification and regression tree analysis. Associations between exposure thresholds and clinical outcomes, including AKI and efficacy, were analysed by logistic regression. Dosing recommendations were designed using Monte Carlo simulations based on the optimised exposure target. ResultsPop-PK modelling included 182 neonates with 411 observations. On covariate analysis, neonatal physiological maturation, renal function and concomitant use of vasoactive agents (VAS) significantly affected vancomycin PK. Seven cases of vancomycin-induced AKI were detected. Area under the concentration-time curve from 0–24 hours (AUC0–24) ≥ 485 mg•h/L was an independent risk factor for AKI after adjusting for VAS co-administration. The clinical efficacy of vancomycin was analysed in 42 patients with blood culture-proven staphylococcal sepsis. AUC0–24 to minimum inhibitory concentration (AUC0–24/MIC) ≥ 234 was the only significant predictor of clinical effectiveness. Monte Carlo simulations indicated that regimens in Neonatal Formulary 7 and Red Book (2018) were unsuitable for all neonates. ConclusionAn AUC0–24 of 240–480 (assuming MIC = 1 mg/L) is a recommended exposure target of vancomycin in neonates. Model-informed dosing regimens are valuable in clinical practice.