Division of Clinical Pharmacology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, MLC6018, Cincinnati, OH, 45229-3039, USA.
Department of Pediatrics, College of Medicine, University of Cincinnati, Cincinnati, OH, USA.
Clin Pharmacokinet. 2019 Jun;58(6):793-803. doi: 10.1007/s40262-018-0729-3.
Milrinone is used for the prevention of low cardiac output syndrome in pediatric patients after cardiac surgery. Milrinone is mainly eliminated by the kidneys; however, there is limited information on milrinone pharmacokinetics in infants who have acute kidney injury (AKI). The aim of this study was to develop a milrinone population pharmacokinetic model in neonates and infants with or without AKI. The developed milrinone pharmacokinetic model was utilized for a Monte Carlo simulation analysis to identify age-appropriate dosing regimens in neonates and infants.
Population pharmacokinetic analysis was performed with a total of 1088 serum milrinone concentrations obtained from 92 infants as part of a prospective clinical study in neonates and infants following cardiac surgery (ClinicalTrials.gov identifier NCT01966237). AKI stages were determined based on the Kidney Injury Improving Global Outcomes (KDIGO) Clinical Practice Guideline within the first three postoperative days.
A two-compartment model was found to adequately describe the pharmacokinetic data. Allometrically scaled body weight, AKI stages, and maturation function were identified as significant predictors of milrinone clearance. The proposed dosing regimens for milrinone continuous infusions were determined based on a target concentration attainment of simulated steady-state concentration and covered three age groups across 0-12 months of age for each AKI stage.
This study provides a milrinone population pharmacokinetic model in neonates and infants and captures the developmental changes in clearance. Age-appropriate dosing regimens were determined based on the simulation analysis with the developed pharmacokinetic model. The findings will facilitate model-informed precision dosing of milrinone in infants with or without AKI.
米力农被用于预防心脏手术后儿科患者的低心输出综合征。米力农主要通过肾脏消除；然而，在患有急性肾损伤（AKI）的婴儿中，米力农药代动力学的信息有限。本研究旨在建立有无 AKI 的新生儿和婴儿米力农群体药代动力学模型。所建立的米力农药代动力学模型用于蒙特卡罗模拟分析，以确定新生儿和婴儿的适宜年龄给药方案。
对总共 92 例婴儿在心脏手术后的前瞻性临床研究中获得的 1088 个米力农血清浓度进行群体药代动力学分析（ClinicalTrials.gov 标识符 NCT01966237）。在术后前三天，根据肾脏损伤改善全球结局（KDIGO）临床实践指南确定 AKI 分期。
发现两室模型能够很好地描述药代动力学数据。比例体重、AKI 分期和成熟功能被确定为米力农清除率的重要预测因子。基于模拟稳态浓度的目标浓度达到和覆盖每个 AKI 分期 0-12 个月龄的三个年龄组，确定了米力农持续输注的推荐给药方案。
本研究提供了新生儿和婴儿米力农的群体药代动力学模型，并捕捉了清除率的发育变化。基于开发的药代动力学模型的模拟分析确定了适合年龄的给药方案。这些发现将有助于在有或没有 AKI 的婴儿中进行米力农的模型指导精准给药。
