Department of Pharmacology and Clinical Pharmacology, University of Auckland, Auckland, New Zealand.
Department of Anaesthesia, Auckland Hospital, Auckland, New Zealand.
Clin Pharmacokinet. 2024 May;63(5):695-706. doi: 10.1007/s40262-024-01372-5. Epub 2024 Apr 13.
Milrinone is an inotrope and vasodilator used for prophylaxis or treatment of low cardiac output syndrome after weaning from cardiopulmonary bypass (CPB). It is renally eliminated and has an acceptable therapeutic range of 100-300 μg/L, but weight-based dosing alone is associated with poor target attainment. We aimed to develop a population pharmacokinetic model for milrinone from premature neonates to adolescents, and to evaluate how age, renal function and recovery from CPB may impact dose selection.
Fifty paediatric patients (aged 4 days to 16 years) were studied after undergoing cardiac surgery supported by CPB. Data from 29 premature neonates (23-28 weeks' postmenstrual age) treated for prophylaxis of low systemic blood flow were available for a pooled pharmacokinetic analysis. Population parameters were estimated using non-linear mixed effects modelling (NONMEM 7.5.1).
There were 369 milrinone measurements available for analysis. A one-compartment model with zero-order input and first-order elimination was used to describe milrinone disposition. Population parameters were clearance 17.8 L/70 kg [95% CI 15.8-19.9] and volume 20.4 L/h/70 kg [95% CI 17.8-22.1]. Covariates included size, postmenstrual age and renal function for clearance, and size and postnatal age for volume. Milrinone clearance is reduced by 39.5% [95% CI 24.0-53.7] immediately after bypass, and recovers to baseline clearance with a half-time of 12.0 h [95% CI 9.7-15.2]. Milrinone volume was 2.07 [95% CI 1.87-2.27] times greater at birth than the population standard and decreased over the first days of life with a half-time of 0.977 days [95% CI 0.833-1.12].
Milrinone is predominately renally eliminated and so renal function is an important covariate describing variability in clearance. Increasing clearance over time likely reflects increasing cardiac output and renal perfusion due to milrinone and return to baseline following CPB.
米力农是一种正性肌力药和血管扩张剂，用于体外循环（CPB）脱机后预防或治疗低心输出综合征。它通过肾脏消除，治疗范围可接受的为 100-300μg/L，但仅基于体重的给药与目标达标不良有关。我们旨在建立米力农在早产儿到青少年人群中的群体药代动力学模型，并评估年龄、肾功能和 CPB 恢复如何影响剂量选择。
50 名接受 CPB 支持的心脏手术后的儿科患者参与了这项研究。29 名接受预防性治疗低全身血流的早产儿（胎龄 23-28 周）的数据可用于合并药代动力学分析。使用非线性混合效应模型（NONMEM 7.5.1）估算群体参数。
共有 369 个米力农测量值可用于分析。采用一室模型，零级输入和一级消除来描述米力农的分布。群体参数为清除率 17.8 L/70kg[95%CI 15.8-19.9]和容积 20.4 L/h/70kg[95%CI 17.8-22.1]。清除率的协变量包括大小、胎龄和肾功能，而容积的协变量包括大小和出生后年龄。CPB 后米力农清除率立即降低 39.5%[95%CI 24.0-53.7]，并在 12.0 小时[95%CI 9.7-15.2]内恢复到基线清除率。米力农的容积在出生时是人群标准的 2.07[95%CI 1.87-2.27]倍，并在生命的头几天逐渐减少，半衰期为 0.977 天[95%CI 0.833-1.12]。
米力农主要通过肾脏消除，因此肾功能是描述清除率变异性的重要协变量。随着时间的推移，清除率的增加可能反映了由于米力农导致的心输出量和肾灌注的增加，以及 CPB 后的恢复至基线水平。
