Lee Dong Hwan, Lee Jae Ha, Jang Ji Hoon, Kim Yong Kyun, Kang Gaeun, Jung So Young, Her Minyoung, Jang Hang Jea
Department of Clinical Pharmacology, Hallym University Sacred Heart Hospital, Hallym University College of Medicine, Anyang, Republic of Korea.
Department of Internal Medicine, Inje University Haeundae Paik Hospital, Inje University College of Medicine, Busan, Republic of Korea.
Front Pharmacol. 2025 May 23;16:1541131. doi: 10.3389/fphar.2025.1541131. eCollection 2025.
To better understand nafamostat mesylate (NM) dose requirements during extracorporeal membrane oxygenation (ECMO), this study investigated its pharmacokinetic/pharmacodynamic (PK/PD) properties by comparing samples from the systemic circulation of patients and from the ECMO circuit. It specifically examined the relationship between NM concentration and activated partial thromboplastin time (aPTT) changes, aiming to provide a foundation for future dosing optimization.
In this prospective study, 24 ECMO patients received a continuous infusion of NM through a dedicated stopcock located before the ECMO pump. This placement targets the anticoagulant effects of NM specifically to the ECMO circuit without substantially affecting the patient's overall coagulation status. The starting dose was 15 mg/h, adjusted to keep the aPTT within a target range of 40-80 s. Blood samples were collected from both the patient's central venous catheter and the ECMO circuit for PK/PD analysis using a nonlinear mixed effects model.
The PK profiles of NM, derived from samples taken from both the patient's catheter and the ECMO circuit, were best described by a two-compartment model. In the PK/PD models, the effect of NM on prolonging aPTT was described using a turnover model. NM was shown to inhibit the decrease in aPTT in the turnover model. In the patient model, the maximum inhibitory effect (Imax) of NM on the reduction of aPTT was 35.5%, and the concentration of NM required to achieve half of this maximum effect (IC50) was 350 μg/L. On the other hand, in the ECMO model, the Imax for aPTT reduction was 43.6%, with an IC50 of 581 μg/L.
The PK/PD models developed from samples collected from both the patient and the ECMO circuit indicate significant differences in PD. Given the observed variability and the high risk of bleeding in ECMO patients, a predictive model incorporating these differences and patient-specific variables could significantly improve anticoagulation management.
为了更好地了解体外膜肺氧合（ECMO）期间甲磺酸萘莫司他（NM）的剂量需求，本研究通过比较患者体循环和ECMO回路中的样本，调查了其药代动力学/药效学（PK/PD）特性。它特别研究了NM浓度与活化部分凝血活酶时间（aPTT）变化之间的关系，旨在为未来的剂量优化提供基础。
在这项前瞻性研究中，24例接受ECMO治疗的患者通过位于ECMO泵之前的专用旋塞持续输注NM。这种放置方式使NM的抗凝作用专门针对ECMO回路，而基本上不影响患者的整体凝血状态。起始剂量为15mg/h，根据需要进行调整以使aPTT保持在40 - 80秒的目标范围内。从患者的中心静脉导管和ECMO回路采集血样，使用非线性混合效应模型进行PK/PD分析。
从患者导管和ECMO回路采集的样本得出的NM的PK曲线，最好用二室模型来描述。在PK/PD模型中，使用周转模型描述了NM对延长aPTT的作用。在周转模型中显示NM可抑制aPTT的降低。在患者模型中，NM对aPTT降低的最大抑制作用（Imax）为35.5%，达到此最大作用一半时所需的NM浓度（IC50）为350μg/L。另一方面，在ECMO模型中，aPTT降低的Imax为43.6%，IC50为581μg/L。
根据从患者和ECMO回路采集的样本建立的PK/PD模型表明，药效学存在显著差异。鉴于观察到的变异性以及ECMO患者出血的高风险，纳入这些差异和患者特定变量的预测模型可显著改善抗凝管理。
