In:
Biopharmaceutics & Drug Disposition, Wiley, Vol. 37, No. 7 ( 2016-10), p. 409-420
Abstract:
The development of inhibitory antibodies against factor VIII (FVIII) is a major challenge in hemophilia A (HA) therapy. Such antibodies develop in nearly 30% of patients receiving replacement FVIII, abrogating therapeutic efficacy. This work evaluated whether B‐domain deleted FVIII encapsulated in phosphatidylinositol containing lipid nanoparticles (PI‐BDD FVIII) could serve as an efficacious FVIII replacement therapy in the presence of inhibitors. The HA mice were given clinically relevant doses of FVIII to develop inhibitors. The efficacy of free and PI‐BDD FVIII was studied in inhibitor‐positive HA mice using a tail clip assay. Mathematical modeling of these data was conducted to evaluate the hypothesis that lipid association sterically shields the protein from inhibitor binding. The immunization protocol resulted in a mean inhibitory titer level of 198 ± 52 BU/ml. Free BDD FVIII was ineffective at controlling blood loss in inhibitor‐positive HA mice as early as 2 h post dose. In contrast, PI‐BDD FVIII treated animals retained partial hemostatic efficacy as long as 18 h post dose. Mathematical modeling supports the hypotheses that a greater fraction of lipid‐associated FVIII remains unbound to inhibitors and that PI‐BDD FVIII has lower binding affinity to inhibitors than does the free protein. In addition, the modeling approaches extend current efforts to model the impact of immunogenicity on PK and the therapeutically meaningful endpoint of efficacy, thereby addressing an important knowledge gap, particularly in the FVIII scientific literature. Clinical translation of these findings could result in a significant improvement in the quality of care of inhibitor‐positive HA patients. Copyright © 2016 John Wiley & Sons, Ltd.
Type of Medium:
Online Resource
ISSN:
0142-2782
,
1099-081X
Language:
English
Publisher:
Wiley
Publication Date:
2016
detail.hit.zdb_id:
1496395-4
SSG:
12
SSG:
15,3
Permalink