In vitro and in vivo stability of diluted recombinant factor VIII for continuous infusion use in haemophilia A

Abstract

Factor VIII (FVIII) replacement by continuous infusion (CI) is used postoperatively or after significant bleeding. For young paediatric patients, CI may require FVIII dilution. Variable stabilities of diluted full-length recombinant FVIII Kogenate FS (KG-FS) have been reported under different storage conditions. We investigated the recovery and stability of diluted KG-FS in vitro and in vivo. Kogenate FS was diluted to 50-120 U mL(-1) and its recovery and stability in glass vials or polypropylene syringes was determined. Furthermore, stability of KG-FS diluted to 80 U mL(-1)'administered' via single- and double-pump mock CI systems was tested. Finally, the in vivo stability of KG-FS diluted to approximately 60 U mL(-1) and administered postsurgically by CI with the double-pump to a paediatric patient with severe haemophilia A undergoing implantable venous access device placement was investigated. Initial KG-FS dilution resulted in a 10-20% FVIII loss; a further 25-30% loss occurred over 72 h in vials or syringes. With the double-pump, 1 h recovery was 35%, increasing to 80% by 24 h; the initial losses were because of the Y-infusion of a 10-fold larger volume of saline concomitantly with the FVIII. In vivo, CI resulted in stable FVIII activity levels within the target range. These in vitro results are important for the generation of CI guidelines for diluted KG-FS in the paediatric haemophilic population. That FVIII losses occur upon dilution and with the double-pump does not preclude use of diluted KG-FS. Indeed, stable FVIII levels were maintained when diluted KG-FS was administered by CI with the double-pump to a paediatric patient postsurgically.

Continuous infusion in haemophilia: current practice in Europe

“…Concentrated FVIII solutions retain excellent stability at room temperature over prolonged time periods [4,7,22,23,37] in contrast to the reduced stability of diluted FVIII solutions [36,38,39]. Limited adsorption of FVIII to the walls of some infusion sets material (polypropylene syringes and polyethylene tubing) is suggested to cause initial decrease of activity in diluted solutions [38,39]. This, however, did not appear to affect haemostatic efficacy nor clinical outcome in patients treated with CI [23,39].…”

“…By contrast, 59% and 79% centres in USA and Canada, respectively, dilute reconstituted concentrates in normal saline [29,36]. Concentrated FVIII solutions retain excellent stability at room temperature over prolonged time periods [4,7,22,23,37] in contrast to the reduced stability of diluted FVIII solutions [36,38,39]. Limited adsorption of FVIII to the walls of some infusion sets material (polypropylene syringes and polyethylene tubing) is suggested to cause initial decrease of activity in diluted solutions [38,39].…”

Continuous Infusion of Coagulation Products in Hemophilia

“…Revel-Vilk et al [22] demonstrated that these in-vitro losses of FVIII did not diminish the efficacy of CI in vivo. CI of rFVIII-FS diluted to 80 U/mL with 0.9% saline administered with a syringe pump to a boy with severe hemophilia postsurgically resulted in stable FVIII activity levels within the target range [22]. Nevertheless, before initiating CI it is advisable to test the stability of each concentrate type and to assay its compatibility with the particular infusion set to be used for CI.…”

“…However, in contrast to an excellent stability of undiluted rFVIII-FS for more than 7 days (Figure 29.2) [16], the dilution further than by the regular reconstitution resulted in initial loss of activity and decreased stability of product stored in the vials or syringes (Figure 29.3) [21,22]. Revel-Vilk et al [22] demonstrated that these in-vitro losses of FVIII did not diminish the efficacy of CI in vivo. CI of rFVIII-FS diluted to 80 U/mL with 0.9% saline administered with a syringe pump to a boy with severe hemophilia postsurgically resulted in stable FVIII activity levels within the target range [22].…”

Nacionalna priporočila za obravnavo bolnikov s hemofilijo

“…Infuzijsko hitrost lahko nato hitrost infuzije (ie/kg/uro) očistek (ml/kg/uro) = izmerjena aktivnost faktorja (ie/ml) določimo z vsakodnevnim računanjem očistka ali pa po obrazcu neposredno izračunamo hitrost v ml/uro. Izbrani koagulacijski faktor se pripravi po priloženih navodilih proizvajalca brez dodatnega redčenja (pri zelo majhni količini topila v viali se redči s fiziološko raztopino) (63). Za prepreči-tev tromboflebitisa na perifernih venah se koagulacijskemu faktorju doda 4 E/ ml heparina.…”