Pharmacokinetics and pharmacodynamics of low doses of recombinant tissue plasminogen activator to establish a model for biosimilarity comparisons

• Published in: Research and practice in thrombosis and haemostasis 2024-08, Vol.8 (6), p.102518, Article 102518
• Main Authors: Derhaschnig, Ulla, Buchtele, Nina, Steiner, Margarete M., Drucker, Christa, Firbas, Christa, Schörgenhofer, Christian, Gelbenegger, Georg, König, Franz, Jilma, Bernd, Kovacevic Miljevic, Katarina D.
• Format: Article
• Language: English
• Subjects: clinical trial; Original; pharmacodynamics; pharmacokinetics; thrombolytic therapy; tissue plasminogen activator
• ISSN: 2475-0379; 2475-0379
• DOI: 10.1016/j.rpth.2024.102518

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 (