First-in-Human Evaluation of Anti–von Willebrand Factor Therapeutic Aptamer ARC1779 in Healthy Volunteers
| Autor: | Thomas V. Holohan, Christopher J. Horvath, Tia DeFeo-Fraulini, H. Nicholas Marsh, Robert G. Schaub, Sleiman BouFakhreddine, James C. Gilbert, Judith M. Healy, Renta Hutabarat, Patricia G. Merlino |
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| Rok vydání: | 2007 |
| Předmět: |
Adult
Male medicine.medical_specialty Time Factors Adolescent Platelet Function Tests Blood volume Double-Blind Method Fibrinolytic Agents Pharmacokinetics Von Willebrand factor Physiology (medical) Internal medicine von Willebrand Factor medicine Humans Distribution (pharmacology) Platelet Acute Coronary Syndrome Aged Dose-Response Relationship Drug biology business.industry Area under the curve Antagonist Aptamers Nucleotide Middle Aged Protein Structure Tertiary Endocrinology Platelet Glycoprotein GPIb-IX Complex Pharmacodynamics biology.protein Female Cardiology and Cardiovascular Medicine business |
| Zdroj: | Circulation. 116:2678-2686 |
| ISSN: | 1524-4539 0009-7322 |
| DOI: | 10.1161/circulationaha.107.724864 |
| Popis: | Background— ARC1779 is a therapeutic aptamer antagonist of the A1 domain of von Willebrand Factor (vWF), the ligand for receptor glycoprotein 1b on platelets. ARC1779 is being developed as a novel antithrombotic agent for use in patients with acute coronary syndromes. Methods and Results— This was a randomized, double-blind, placebo-controlled study in 47 healthy volunteers of doses of ARC1779 from 0.05 to 1.0 mg/kg. Pharmacodynamic effects were measured by an ELISA for free vWF A1 binding sites and by a platelet function analyzer. In terms of pharmacokinetics, the concentration-time profile of ARC1779 appeared monophasic. The observed concentration and area under the curve were dose proportional. The mean apparent elimination half-life was ≈2 hours, and mean residence time was ≈3 hours. The mean apparent volumes of distribution (at steady state and during terminal phase) were approximately one half the blood volume, suggesting that ARC1779 distribution is in the central compartment. The mean clearance ranged from ≈10% to ≈21% of the glomerular filtration rate, suggesting that renal filtration may not be a major mechanism of clearance of ARC1779. Inhibition of vWF A1 binding activity was achieved with an EC 90 value of 2.0 μg/mL (151 nmol/L) and of platelet function with an EC 90 value of 2.6 μg/mL (196 nmol/L). ARC1779 was generally well tolerated, and no bleeding was observed. Adverse events tended to be minor and not dose related. Conclusions— This is the first-in-human evaluation of a novel aptamer antagonist of vWF. ARC1779 produced dose- and concentration-dependent inhibition of vWF activity and platelet function with duration of effect suitable for the intended clinical use in acute coronary syndromes. |
| Databáze: | OpenAIRE |
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