Pharmacological dose of recombinant FVIIa acts via Tissue Factor mechanism in vitro

Tuesday, October 09, 2012 — Poster Session I
1:00 p.m. – 3:00 p.m	Natcher Conference Center, Building 45	FDA/CBER	BIOCHEM-15

Authors

• SA Woodle
• AM Shibeko
• MV Ovanesov

Abstract

Supraphysiological doses of Recombinant Factor VIIa (rFVIIa), licensed for the treatment of bleeding in hemophilia patients with inhibitors, continue to be used safely despite a limited knowledge of its mechanism of action and an ongoing debate over appropriate dosing. Peak plasma concentrations of rFVIIa range from 10-25 nM and drop to 5-15 nM two hours post infusion, at which time a second dose is recommended. Fluorogenic substrate-based thrombin generation (TG) and clotting in FVII-deficient plasma were used to determine the dose response of rFVIIa in vitro. We found that rFVIIa action is mediated independently by procoagulant phospholipids and TF. rFVIIa doses greater than 50 nM, i.e. above the pharmacological range, were needed to drive phospholipid-dependent TG, and the response curve was qualitatively steep. In contrast, TF-induced contribution reached saturation after 10 nM. Zymogen FVII was found to inhibit TF-dependent contributions when initiated by both TF-bearing cells and lipid vesicles at low TF concentrations and low TF surface-density conditions, suggesting the drug efficacy may depend on the amount of FVII in circulation. We conclude that the pharmacological action of licensed rFVIIa doses likely follows a TF-dependent mechanism, and saturation of the hemostatic effect could explain the relative safety of the drug.

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