Premium
Recombinant factor VIII Fc fusion protein: extended‐interval dosing maintains low bleeding rates and correlates with von W illebrand factor levels
Author(s) -
Shapiro A. D.,
Ragni M. V.,
Kulkarni R.,
Oldenberg J.,
Srivastava A.,
Quon D. V.,
Pasi K. J.,
Hanabusa H.,
Pabinger I.,
Mahlangu J.,
Fogarty P.,
Lillicrap D.,
Kulke S.,
Potts J.,
Neelakantan S.,
Nestorov I.,
Li S.,
Dumont J. A.,
Jiang H.,
Brennan A.,
Pierce G. F.
Publication year - 2014
Publication title -
journal of thrombosis and haemostasis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.947
H-Index - 178
eISSN - 1538-7836
pISSN - 1538-7933
DOI - 10.1111/jth.12723
Subject(s) - von willebrand factor , dosing , recombinant dna , medicine , interval (graph theory) , gastroenterology , platelet , chemistry , mathematics , biochemistry , combinatorics , gene
Summary Background Routine prophylaxis with replacement factor VIII (FVIII) – the standard of care for severe hemophilia A – often requires frequent intravenous infusions (three or four times weekly). An FVIII molecule with an extended half‐life could reduce infusion frequency. The A‐LONG study established the safety, efficacy and prolonged pharmacokinetics of recombinant FVIII Fc fusion protein ( rFVIIIF c) in previously treated adolescents and adults with severe hemophilia A. Objective In this post hoc analysis, we investigated the relationship between subjects' prestudy (FVIII) and on‐study ( rFVIIIF c) regimens. Methods We analyzed two subgroups of subjects: prior prophylaxis and on‐study individualized prophylaxis ( n = 80), and prior episodic treatment and on‐study weekly prophylaxis ( n = 16). Subjects' prestudy dosing regimens and bleeding rates were compared with their final rFVIIIF c regimens and annualized bleeding rates (ABRs) in the last 3 months on‐study. Dosing regimen simulations based on population pharmacokinetics models for rFVIII and rFVIIIF c were performed. Results As compared with their prestudy regimen, 79 of 80 (98.8%) subjects on individualized rFVIIIF c prophylaxis decreased their infusion frequency. Overall ABRs were low, with comparable factor consumption. Longer dosing intervals, including 5‐day dosing, were associated with higher baseline von Willebrand factor antigen levels. Simulated dosing regimens predicted a greater proportion of subjects with steady‐state FVIII activity trough levels of ≥ 1 IU dL −1 (1%) with rFVIIIF c than with equivalent rFVIII regimens. Conclusion These results suggest that patients on rFVIIIF c prophylaxis can reduce their infusion frequency as compared with their prior FVIII regimen while maintaining low bleeding rates, affording more patients trough levels of ≥ 1 IU dL −1 than with rFVIII products requiring more frequent dosing regimens.