Single‐dose pharmacokinetics of porcine factor VIII (Hyate C)

Abstract

The objective was to establish the pharmacokinetic properties of porcine factor VIII (pFVIII) at three different doses in a single patient. The patient, born in 1952, had severe haemophilia A and developed an inhibitor to human FVIII (hFVIII) in 1966 aged 14 years. He was first treated with pFVIII in 1980. Apart from a short period of treatment with hFVIII in 1998 which resulted in the reappearance of the inhibitor, pFVIII has been constantly used since 1984. No inhibitor against human or porcine FVIII had been recordable over the 2-year period prior to the study. Three separate pharmacokinetic studies were performed using a washout period of 72 h and doses of 10 U kg (-1), 25 U kg (-1), or 50 U kg (-1), respectively, with sampling at preinfusion, then at 15 and 30 min and 1, 3, 6, 9, 12 and 24 h postinfusion. The FVIII levels were measured using both plasma derived one stage APTT based assay and chromogenic assay. The results were computed using a model-independent analysis and a model-dependent analysis. The respective clearances (mL h(-1)kg(-1)) at doses 50 U, 25 U or 10 U kg (-1) were 1.32, 1.33 1.8 (bioassay) and 2.54, 2.93, 9.43 (chromogenic). The respective half-lives (h) at doses 50 U, 25 U, and 10 U kg (-1) were 23.71, 16.54, 25.17 (bioassay) and 15.71, 17.39, and 10.66 (chromogenic). The respective recoveries (u dL(-1)/u kg(-1)) at doses 50 U, 25 U, and 10 U kg (-1) were 2.32, 2.44, 2.7 (bioassay) and 1.42, 1.16 and 0.9 (chromogenic). It was found that the two compartment model best fitted the curves of the bioassay and a one compartmental model best fitted the curves of the chromogenic assay. The pharmacokinetic studies are the first to be performed at different dose levels and using different assay methods for pFVIII. Using the bioassay, they show a long half-life and high recovery compared to hFVIII. The differences between the bioassay and the chromogenic assay reflect their different biological basis and are of relevance when potency labelling is performed using chromogenic assay (European Pharmacopeia).

Pharmacokinetics and safety of OBI‐1, a recombinant B domain‐deleted porcine factor VIII, in subjects with haemophilia A

“…The difference between the results of the two assays was smaller in subjects receiving OBI‐1: OSCA yielded higher results in two of the three subjects who received OBI‐1 (15% and 45% higher vs. the chromogenic assay), and the remaining subject had 35% higher results with the chromogenic assay compared with OSCA. A discrepancy between FVIII results using OSCA and the chromogenic assay in patients receiving Hyate:C has been previously reported [13], and may reflect not only differences in the assay properties, but also differences in the properties and purity of porcine FVIII. Unfortunately, this study was stopped early because Hyate:C was no longer available.…”

Porcine factor VIII

“…The reason for the selection of a porcine product in such cases was often concern about the possibility of transmission of human blood‐borne infections at a time of heightened insecurity over the safety of plasma‐derived human concentrates, when recombinant products were not yet available. The half‐life of porcine factor VIII in patients with no detectable inhibitor was reported to be very similar to that of human factor VIII and in the range 8–12 h [6,10,12].…”

The Evidence behind Inhibitor Treatment with Porcine Factor VIII

“…In addition, FVIII levels measured using the chromogenic assay are on average 50% lower than those measured by the one-stage method [7]. The mechanism for this observation has not been clarified.…”