Derhaschnig Ulla, Buchtele Nina, Steiner Margarete M, Drucker Christa, Firbas Christa, Schörgenhofer Christian, Gelbenegger Georg, König Franz, Jilma Bernd, Kovacevic Miljevic Katarina D
Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria.
Department of Emergency Medicine, Medical University of Vienna, Vienna, Austria.
Res Pract Thromb Haemost. 2024 Jul 22;8(6):102518. doi: 10.1016/j.rpth.2024.102518. eCollection 2024 Aug.
Recombinant tissue plasminogen activator (rt-PA) is a thrombolytic agent and essential in emergency medical care. Given recent supply shortages, the availability of biosimilar products is an urgent medical need. However, biosimilarity trials are difficult to perform in critically ill patients.
The aim of this pilot study was to investigate the pharmacokinetics and pharmacodynamics of low rt-PA doses to establish a model for testing proposed biosimilars in healthy volunteers.
Eight healthy volunteers received 0.02 to 0.05 mg/kg rt-PA on 3 study days; blood samples were obtained every 4 minutes after the end of the bolus infusion to measure rt-PA antigen levels by enzyme immunoassay, and the pharmacodynamics were assessed with rotational thromboelastometry.
Bolus infusion of low rt-PA doses was safe and well tolerated. Maximal plasma concentrations and the area under the curve increased dose-dependently. Time-concentration curves were clearly separated between the lower and the higher doses. As expected, the half-live of rt-PA was short (4.5-5 min), and representative for therapeutic doses. The intrasubject coefficient variations were moderate (<25%). Bolus infusion of rt-PA dose-dependently shortened lysis time and lysis onset time in both dose groups and caused maximum clot lysis of 100% in all participants.
In conclusion, the pharmacokinetics of rt-PA was dose linear and displayed limited intrasubject variability even at subtherapeutic doses. The half-life and thus clearance of rt-PA was representative of full therapeutic doses. The lysis time was shortened in a dose and time-dependent fashion and was clearly distinguishable between doses. Thus, the model appears to be suitable and sensitive to test biosimilarity.
重组组织型纤溶酶原激活剂（rt-PA）是一种溶栓剂，在急诊医疗中至关重要。鉴于近期供应短缺，生物类似药产品的可及性成为一项迫切的医疗需求。然而，生物相似性试验在重症患者中难以开展。
这项初步研究的目的是调查低剂量rt-PA的药代动力学和药效学，以建立一个在健康志愿者中测试拟用生物类似药的模型。
8名健康志愿者在3个研究日接受了0.02至0.05mg/kg的rt-PA；在推注输注结束后每隔4分钟采集血样，通过酶免疫测定法测量rt-PA抗原水平，并采用旋转血栓弹力图评估药效学。
低剂量rt-PA的推注输注安全且耐受性良好。最大血浆浓度和曲线下面积呈剂量依赖性增加。较低剂量和较高剂量之间的时间-浓度曲线明显分开。正如预期的那样，rt-PA的半衰期较短（4.5 - 5分钟），代表治疗剂量。受试者内系数变异适中（<25%）。rt-PA的推注输注在两个剂量组中均呈剂量依赖性缩短溶解时间和溶解起始时间，并使所有参与者达到100%的最大凝块溶解率。
总之，rt-PA的药代动力学呈剂量线性，即使在亚治疗剂量下受试者内变异性也有限。rt-PA的半衰期及清除率代表了全治疗剂量情况。溶解时间以剂量和时间依赖性方式缩短，且不同剂量之间有明显区分度。因此，该模型似乎适用于测试生物相似性且具有敏感性。
