Datasheet1_Pragmatic physiologically-based pharmacokinetic modeling to support clinical implementation of optimized gentamicin dosing in term neonates and infants: proof-of-concept.docx

IntroductionModeling and simulation can support dosing recommendations for clinical practice, but a simple framework is missing. In this proof-of-concept study, we aimed to develop neonatal and infant gentamicin dosing guidelines, supported by a pragmatic physiologically-based pharmacokinetic (PBPK) modeling approach and a decision framework for implementation.MethodsAn already existing PBPK model was verified with data of 87 adults, 485 children and 912 neonates, based on visual predictive checks and predicted-to-observed pharmacokinetic (PK) parameter ratios. After acceptance of the model, dosages now recommended by the Dutch Pediatric Formulary (DPF) were simulated, along with several alternative dosing scenarios, aiming for recommended peak (i.e., 8–12 mg/L for neonates and 15–20 mg/L for infants) and trough (i.e.,

本研究的宗旨在于构建新生儿及婴儿用庆大霉素的剂量推荐指南，该指南得以通过一种基于生理药代动力学（PBPK）的实用建模方法以及实施决策框架的支持而形成。研究方法上，我们验证了一个现有的PBPK模型，该模型基于87名成人、485名儿童和912名新生儿的实验数据，通过视觉预测检验和预测-观察药代动力学（PK）参数比率进行验证。模型通过验证后，对荷兰儿科药典（DPF）当前推荐的剂量进行了模拟，同时考虑了多种替代剂量方案，旨在达到推荐的峰浓度（即新生儿8-12毫克/升，婴儿15-20毫克/升）和谷浓度水平。