Takeuchi Masanobu, Tanoshima Reo, Miyagawa Naoyuki, Sarashina Takeo, Kato Hiromi, Kajiwara Ryosuke, Ito Shinya, Goto Hiroaki
Department of Pediatrics, Yokohama City University Hospital, Yokohama, Japan.
Division of Clinical Pharmacology and Toxicology, The Hospital for Sick Children, Toronto, Canada.
Pediatr Blood Cancer. 2017 Mar;64(3). doi: 10.1002/pbc.26234. Epub 2016 Oct 12.
Thrombomodulin alfa (TM-α) is a new class of anticoagulant drug for patients with disseminated intravascular coagulation (DIC). This study aimed to determine the pharmacokinetics of TM-α and determine the optimal dose in pediatric patients with hematological malignancy and DIC.
Pediatric patients with hematological malignancy and DIC were administered TM-α at a dose of 0.06 mg/kg (380 U/kg) over 30 min every 24 hr. Blood samples were taken at steady state before the start, immediately after the end, and 24 hr after the start of the sixth administration. Population pharmacokinetic analysis was performed using sparse samples with the nonlinear mixed-effect modeling program NONMEM , version 7.3.
The actual and predicted plasma concentrations of TM-α based on the final population pharmacokinetic model showed a good linear correlation. Clearance and volume of distribution of TM-α were affected by body weight. The clearance of TM-α in pediatric patients with hematological malignancy and DIC was higher than that in adults as previously reported. Six of eight patients did not achieve the target trough concentration at steady state. Furthermore, the pharmacokinetic simulation based on the estimated pharmacokinetic parameters from the final model demonstrated that TM-α administered at a dose of 0.06 mg/kg every 24 hr also failed to achieve the target trough concentration at steady state in the majority of pediatric patients.
Our study shows that further dose adjustment of TM-α is necessary considering the higher clearance per body weight in pediatric patients with hematological malignancy and DIC.
血栓调节蛋白α（TM-α）是一种用于弥散性血管内凝血（DIC）患者的新型抗凝药物。本研究旨在确定TM-α在血液系统恶性肿瘤合并DIC的儿科患者中的药代动力学，并确定最佳剂量。
血液系统恶性肿瘤合并DIC的儿科患者每24小时接受一次TM-α静脉输注，剂量为0.06 mg/kg（380 U/kg），输注时间为30分钟。在开始第六次给药前的稳态、给药结束后即刻以及开始给药后24小时采集血样。使用非线性混合效应建模程序NONMEM 7.3对稀疏样本进行群体药代动力学分析。
基于最终群体药代动力学模型的TM-α实际血浆浓度和预测血浆浓度显示出良好的线性相关性。TM-α的清除率和分布容积受体重影响。血液系统恶性肿瘤合并DIC的儿科患者中TM-α的清除率高于先前报道的成人患者。8名患者中有6名在稳态时未达到目标谷浓度。此外，基于最终模型估计的药代动力学参数进行的药代动力学模拟表明，在大多数儿科患者中，每24小时给予0.06 mg/kg的TM-α在稳态时也未能达到目标谷浓度。
我们的研究表明，考虑到血液系统恶性肿瘤合并DIC的儿科患者每单位体重清除率较高，有必要进一步调整TM-α的剂量。
