Khayat Claudia Djambas, Navarro-Puerto Jordi, Ross Cecil Reuben, Subramanian Kannan, Kalappanavar Nijalingappa K, Rucker Karen, Liang Wei, Mondou Elsa
Department of pediatrics, Hotel Dieu de France Hospital Beirut, Saint Joseph University, Lebanon.
Grifols Bioscience Research Group, Grifols, Barcelona, Spain.
Blood Coagul Fibrinolysis. 2023 Jan 1;34(1):61-69. doi: 10.1097/MBC.0000000000001182. Epub 2022 Dec 9.
Congenital afibrinogenemia treatment with plasma-derived fibrinogen concentrates in pediatric patients is limited. This study investigated the pharmacokinetics, surrogate efficacy, and safety of a plasma-derived fibrinogen concentrate (FIB Grifols) in pediatric patients with congenital afibrinogenemia.
Patients aged <18 years old diagnosed with congenital afibrinogenemia were included in this prospective, multinational, phase 1-2, single-arm study. After a single dose of a plasma-derived fibrinogen concentrate (70 mg/kg body weight), pharmacokinetic parameters were determined from plasma fibrinogen activity (Clauss method) and antigen method (ELISA), and calculated by noncompartmental and population pharmacokinetic (popPK) models. Patients were followed up over 14 days. Efficacy variables were the mean change on thromboelastographic variables (maximum clot firmness [MCF], alpha angle [ α ]) and coagulation tests (prothrombin time, activated partial thromboplastin time, and thrombin time) 1 h postinfusion. Safety parameters were assessed.
Eleven patients with a median (range) age 8.80 (3.7-12.7) years were treated with the plasma-derived fibrinogen concentrate. Using the popPK modeling, fibrinogen activity reached a mean (standard deviation) Cmax of 1.3 (0.225) g/l, half-life ( t1/2 ) of 60.6 (4.48) h and incremental in vivo recovery (IVR) of 1.86 (0.322) (mg/dl)/(mg/kg). Surrogate efficacy was demonstrated by significant increase in MCF (9.23 [3.94] mm; P < 0.001; 95% confidence interval 6.58, 11.87). All coagulation times were significantly shortened after fibrinogen concentrate infusion. Adverse events were mild or moderate in severity, and unrelated to fibrinogen concentrate.
In pediatric patients with congenital afibrinogenemia, plasma-derived fibrinogen concentrate revealed a favorable and specific pharmacokinetic profile, demonstrated efficacy in coagulation and was safe and well tolerated.
儿科患者先天性无纤维蛋白原血症采用血浆源性纤维蛋白原浓缩物治疗的情况有限。本研究调查了血浆源性纤维蛋白原浓缩物（Grifols纤维蛋白原）在先天性无纤维蛋白原血症儿科患者中的药代动力学、替代疗效和安全性。
本前瞻性、多国、1-2期单臂研究纳入了年龄<18岁且诊断为先天性无纤维蛋白原血症的患者。单次给予血浆源性纤维蛋白原浓缩物（70mg/kg体重）后，根据血浆纤维蛋白原活性（Clauss法）和抗原法（ELISA）测定药代动力学参数，并通过非房室模型和群体药代动力学（popPK）模型进行计算。对患者进行14天的随访。疗效变量为输注后1小时血栓弹力图变量（最大血凝块硬度[MCF]、α角[α]）和凝血试验（凝血酶原时间、活化部分凝血活酶时间和凝血酶时间）的平均变化。评估安全性参数。
11例年龄中位数（范围）为8.80（3.7-12.7）岁的患者接受了血浆源性纤维蛋白原浓缩物治疗。使用popPK模型，纤维蛋白原活性的平均（标准差）Cmax为1.3（0.225）g/l，半衰期（t1/2）为60.6（4.48）小时，体内增量回收率（IVR）为1.86（0.322）（mg/dl）/（mg/kg）。MCF显著增加（9.23[3.94]mm；P<0.001；95%置信区间6.58，11.87）证明了替代疗效。输注纤维蛋白原浓缩物后，所有凝血时间均显著缩短。不良事件严重程度为轻度或中度，且与纤维蛋白原浓缩物无关。
在先天性无纤维蛋白原血症的儿科患者中，血浆源性纤维蛋白原浓缩物显示出良好且特异的药代动力学特征，在凝血方面显示出疗效，且安全且耐受性良好。
