Department of Clinical Pharmacology and Pharmacoepidemiology, UniversitätsKlinikum Heidelberg, Heidelberg, Germany.
Pediatric Clinical-Pharmacological Trial Centre, UniversitätsKlinikum Heidelberg, Heidelberg, Germany.
BMJ Paediatr Open. 2023 Jan;7(1). doi: 10.1136/bmjpo-2022-001662.
Direct oral anticoagulants (DOACs) are direct inhibitors of coagulation factor Xa and are frequently used in adults for different indications such as deep vein thrombosis or non-valvular atrial fibrillation. Paediatric patients might benefit as well from DOACs because the simplicity and convenience of their use is likely to decrease physical and psychological stress related to invasive procedures associated with phenprocoumon and heparin therapy. Thus, it is expected that the future use of DOACs will ultimately improve compliance and overall safety of anticoagulant therapies in paediatric populations. To assure safe and effective use the clinical pharmacology and pharmacokinetics (PK) of these drugs need to be evaluated in children.
This study is a single-centre, open-label, clinical trial in a paediatric population with non-cyanotic congenital heart defects. After having obtained informed consent from the parents, each participant will receive a single oral administration of a drinkable solution of a microdose cocktail of three FXa inhibitors consisting of apixaban (12.5 µg), rivaroxaban (12.5 µg), edoxaban (50 µg), plus a microdose of the two probe drugs midazolam (10 µg) and yohimbine (25 µg). Serial blood samples (n=up to 20) will be collected at specified time points before and up to 25 hours after cocktail administration. The primary PK endpoint will be the area under the plasma concentration time curve of apixaban, rivaroxaban and edoxaban. Secondary PK outcomes will be C, t, t, Cl/F and V/F. Safety and tolerability of the microdose cocktail will be evaluated as well by a collection of adverse events.
This study has been approved by the responsible Ethics Committee of the Medical Faculty of Heidelberg University.
Study results will be presented at international scientific meetings and published in peer-reviewed journals.
EudraCT 2019-001759-38 16, DRKS00021455.
直接口服抗凝剂（DOACs）是凝血因子 Xa 的直接抑制剂，常用于治疗深静脉血栓形成或非瓣膜性心房颤动等多种适应症。儿科患者也可能从 DOACs 中受益，因为其使用的简便性和便利性可能会降低与华法林和肝素治疗相关的侵入性操作带来的身体和心理压力。因此，预计 DOACs 的未来应用将最终提高儿科人群抗凝治疗的依从性和整体安全性。为确保安全有效使用，需要评估这些药物在儿童中的临床药代动力学（PK）。
这是一项在患有非发绀性先天性心脏缺陷的儿科人群中进行的单中心、开放标签、临床试验。在获得父母的知情同意后，每位参与者将单次口服给予一种微剂量鸡尾酒的可饮用溶液，该鸡尾酒由三种 FXa 抑制剂组成，包括阿哌沙班（12.5μg）、利伐沙班（12.5μg）、依度沙班（50μg），外加两种微剂量探针药物咪达唑仑（10μg）和育亨宾（25μg）。将在鸡尾酒给药前和给药后最多 25 小时内的指定时间点采集（最多 20 例）系列血样。主要 PK 终点将是阿哌沙班、利伐沙班和依度沙班的血浆浓度时间曲线下面积。次要 PK 结局将是 C、t、t、Cl/F 和 V/F。还将通过不良事件的收集来评估微剂量鸡尾酒的安全性和耐受性。
本研究已获得海德堡大学医学系负责伦理委员会的批准。
研究结果将在国际科学会议上发表，并发表在同行评议的期刊上。
EudraCT 2019-001759-38 16，DRKS00021455。
