title: Pharmacokinetics of recombinant factor VIII (recombinate) using one-stage clotting and chromogenic factor VIII assay.
abstract: In a study designed to demonstrate the safety and pharmacokinetics of a recombinant factor VIII (Recombinate) manufactured in Andover, MA and Thousand Oaks, CA, two different methods of factor VIII assay (one-stage clotting and Chromogenic substrate) were compared in vivo. The study was performed in four centres in the UK: London, Oxford, Cardiff and Manchester. Two pharmacokinetic studies, at least one week apart, were performed in 30 patients with severe haemophilia A (VIII:C < 2 IU/dl). A dose of 50 IU/kg was administered with sampling pre-infusion, and +0.25, 0.5, 1, 3, 6, 9, 12 and 24 h post-infusion. The aggregate 60 pharmacokinetic study showed a half-life of 12.7 and 13.0 h (p = 0.28) and recovery of 127 and 161 IU/dl (p = 0.0001) using one-stage clotting or chromogenic substrate respectively. In a supplementary experiment, 20 post-infusion samples were re-assayed by 1-stage and chromogenic assay using two plasma (20th British plasma standard and an "in-house" pooled normal plasma) and two concentrate standards, derived from the same type, but different batch of infused concentrate (Recombinate) and pre-diluted in either individual pre-infusion sample or in pooled commercial haemophilic plasma. The use of the Recombinate concentrate standard overcame the significant difference in FVIII levels between 1-stage and chromogenic assay methods when a plasma standard was used (p <0.0001). It is concluded that where potency dosing designation is carried out by an assay system different to that used in the clinical situation, the use of the recombinant concentrate as a standard in post-infusion plasma samples is likely to give more reliable and reproducible results.
authors.affiliation: Haemophilia Centre and Haemostasis Unit, Royal Free Hospital, London, UK. lee@rfhsm.ac.uk
authors.forename: C A
authors.initials: CA
authors.lastname: Lee
authors.forename: D
authors.initials: D
authors.lastname: Owens
authors.forename: G
authors.initials: G
authors.lastname: Bray
authors.forename: P
authors.initials: P
authors.lastname: Giangrande
authors.forename: P
authors.initials: P
authors.lastname: Collins
authors.forename: C
authors.initials: C
authors.lastname: Hay
authors.forename: E
authors.initials: E
authors.lastname: Gomperts
authors.forename: P
authors.initials: P
authors.lastname: Schroth
authors.forename: T
authors.initials: T
authors.lastname: Barrowcliffe
mesh_terms: D001681:Biological Assay; D001777:Blood Coagulation; D005169:Factor VIII / Q000009:adverse effects / Q000235:genetics / Q000493:pharmacokinetics*; D006801:Humans; D011994:Recombinant Proteins / Q000009:adverse effects / Q000235:genetics / Q000493:pharmacokinetics
chemical_list: D011994:Recombinant Proteins; C078147:F8 protein, human; D005169:Factor VIII