In vitro evaluation of B-domain deleted recombinant factor VIII (ReFacto) stability during simulated continuous infusion administration.
The administration of factor VIII (FVIII) by continuous infusion (CI) to manage severe haemorrhage or during major surgery appears pharmacokinetically and economically favourable when compared with intermittent bolus infusions. Successful clinical use of FVIII delivered by CI, however, requires a thorough assessment of product stability under conditions encountered during CI such as prolonged exposure to the delivery devices at ambient temperature and the low FVIII concentrations. This investigation has identified conditions under which ReFacto, a recombinant human B-domain deleted FVIII, can be successfully delivered under dilute conditions when using large volume parenteral polyvinyl chloride (PVC) bags without the addition of stabilizers or as an undiluted preparation delivered by ambulatory infusion pumps. ReFacto is stable for 36 h when stored in large volume parenteral PVC reservoirs at 3 and 8 IU mL(-1) or 72 h when delivered undiluted at 62 IU mL(-1) by CADD infusion pumps. The greatest concern with the delivery of ReFacto by CI is adsorptive losses to the contact surfaces of the delivery system. There was no significant binding of ReFacto to the PVC reservoirs overtime; however, there was appreciable binding to the administration set under certain conditions. The binding was influenced by the ionic strength of the solution, residence time in the tubing and protein concentration. The recovery and stability profile of ReFacto under certain conditions appears favourable when compared with that of full-length recombinant FVIII products, observed by other investigators.
Neidhardt
E
E
Wyeth BioPharma, Drug Product Development, Andover, MA 01810, USA. eneidhardt@wyeth.com
Koval
R
R
Burke
E
E
Warne
N
N
D000327:Adsorption; D000553:Ambulatory Care / Q000379:methods; D004355:Drug Stability; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005169:Factor VIII / Q000008:administration & dosage* / Q000032:analysis / Q000493:pharmacokinetics; D006467:Hemophilia A / Q000188:drug therapy; D006801:Humans; D007260:Infusion Pumps; D011143:Polyvinyl Chloride; D011994:Recombinant Proteins / Q000008:administration & dosage* / Q000032:analysis / Q000493:pharmacokinetics; D013594:Syringes
D011994:Recombinant Proteins; C427184:recombinant factor VIII SQ; D005169:Factor VIII; D011143:Polyvinyl Chloride