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- Title
Safety, Stability and Pharmacokinetic Properties of Factor Va, a Novel Engineered Coagulation Factor V for Treatment of Severe Bleeding.
- Authors
Gale, Andrew; Bhat, Vikas; Pellequer, Jean-Luc; Griffin, John; Mosnier, Laurent; Drygalski, Annette
- Abstract
Purpose: Activated Factor V (FVa) is a novel engineered FV with excellent prohemostatic efficacy. FVa has three APC cleavage site mutations and an interdomain disulfide bond. Stability, pharmacokinetics, and immunogenic and thrombogenic potential are reported here. Methods: Stability and circulating half-life were determined after incubation in buffer and human plasma, and after injection into FVIII-deficient mice. Immunogenicity potential was assessed by B- and T-cell specific epitope prediction and structural analysis using surface area and atomic depth computation. Thrombogenic potential was determined by quantification of lung fibrin deposition in wild-type mice after intravenous injection of FVa (200 U/kg), recombinant human (rh) Tissue Factor (0.4-16 pmol/kg), rhFVIIa (3 mg/kg) or saline. Results: FVa retained full activity over 30 h in buffer, the functional half-life in human plasma was 4.9 h, and circulating half-life in FVIII-deficient mice was ~30 min. Predicted immunogenicity was not increased compared to human FV. While rh Tissue Factor, the positive control, resulted in pronounced lung fibrin depositions (mean 121 μg/mL), FVa did not (6.7 μg/mL), and results were comparable to fibrin depositions with rhFVIIa (7.6 μg/mL) or saline (5.6 μg/mL). Conclusion: FVa has an appropriate safety and stability profile for further preclinical development as a prohemostatic against severe bleeding.
- Subjects
MEDICATION safety; DRUG stability; BLOOD coagulation factors; HEMORRHAGE treatment; PHARMACOKINETICS
- Publication
Pharmaceutical Research, 2016, Vol 33, Issue 6, p1517
- ISSN
0724-8741
- Publication type
Article
- DOI
10.1007/s11095-016-1895-3