School of Pharmacy, University of Otago, 18 Frederick St, North Dunedin, Dunedin, 9016, New Zealand.
Department of Cardiology, Boston Children's Hospital, Boston, MA, USA.
Clin Pharmacokinet. 2021 Apr;60(4):491-499. doi: 10.1007/s40262-020-00949-0. Epub 2020 Oct 31.
Unfractionated heparin (UFH) dosing and monitoring guidelines for children are often extrapolated from adult data. This practice is suboptimal given the inherent differences in haemostatic maturation and drug handling in children compared with adults.
The aim of this work was to investigate the impact of haemostatic system maturation on the dose-response relationship of UFH in children.
A quantitative model for haemostasis in adults was adapted to account for maturation in UFH pharmacokinetic (PK) parameters with and without age-related changes in coagulation factor concentrations. The adult and adapted models were used to predict the time courses of anti-factor Xa activity (aXa) and activated partial thromboplastin time (aPTT) in patients receiving UFH infusion. Predictions from both models were compared with observed aXa and aPTT measurements from 31 paediatric patients receiving UFH during extracorporeal membrane oxygenation (ECMO).
The model with maturation for both UFH PK and the haemostatic system had an improved aXa and aPTT predictive performance compared with maturation in UFH PK only and the original adult model. Despite the minor effect of haemostatic system maturation on baseline aPTT, it led to substantial changes in the time course of aPTT sensitivity to UFH. This finding suggests that between-subject variability in clotting factors concentrations is potentially a major contributor to the overall variability of aPTT response to UFH. In addition, time-varying clotting factors concentrations may explain within-subject changes in aPTT sensitivity to UFH.
We developed the first quantitative systems pharmacology (QSP) model that provides a mechanistic and quantitative basis for linking physiological and pharmacological maturation to UFH effect and response biomarkers. After appropriate clinical validation, the model could be useful for the development of paediatric-specific individualised UFH dosing recommendations.
未分级肝素（UFH）在儿童中的给药和监测指南通常是从成人数据中推断出来的。鉴于儿童的止血成熟度和药物处理与成人存在内在差异，这种做法并不理想。
本研究旨在探讨止血系统成熟对儿童 UFH 剂量反应关系的影响。
采用一种适用于成人的止血定量模型，该模型考虑了 UFH 药代动力学（PK）参数的成熟度，以及凝血因子浓度是否随年龄变化。使用成人和改编后的模型预测接受 UFH 输注的患者抗因子 Xa 活性（aXa）和活化部分凝血活酶时间（aPTT）的时间过程。比较这两种模型的预测值与 31 例接受 ECMO 期间 UFH 治疗的儿科患者的实测 aXa 和 aPTT 测量值。
与仅成熟 UFH PK 的模型和原始成人模型相比，同时成熟 UFH PK 和止血系统的模型在预测 aXa 和 aPTT 方面具有更好的性能。尽管止血系统成熟对基础 aPTT 的影响较小，但它导致了 aPTT 对 UFH 敏感性的时间过程发生了实质性变化。这一发现表明，凝血因子浓度的个体间变异性可能是 aPTT 对 UFH 反应总体变异性的主要原因。此外，凝血因子浓度的时变可能解释了 UFH 对 aPTT 敏感性的个体内变化。
我们开发了第一个定量系统药理学（QSP）模型，该模型为将生理和药理学成熟与 UFH 效应和反应生物标志物联系起来提供了一种机制和定量基础。经过适当的临床验证后，该模型可用于制定儿科特异性的个体化 UFH 给药建议。
