Potency of high purity factor VIII concentrates

Barrowcliffe, T W; Watton, Jane; Harman, Andrew N.; Tubbs, JillE.; Kemball‐Cook, Geoffrey

doi:10.1016/0140-6736(90)91646-r

Cited by 26 publications

(15 citation statements)

References 3 publications

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“…A discrepancy between one‐stage and chromogenic assay in the assessment of the FVIII potency of high‐purity plasma‐derived concentrates was identified several years ago [10–12,25–28]. The presence of activated FVIII in these products was thought to be the cause of higher potency estimation by one‐stage assay [25–27].…”

Section: Discussionmentioning

confidence: 99%

A multicenter pharmacokinetic study of the B-domain deleted recombinant factor VIII concentrate using different assays and standards

Morfini

Cinotti

Bellatreccia³

et al. 2003

Journal of Thrombosis and Haemostasis

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To cite this article: Mor®ni M, Cinotti S, Bellatreccia A, Paladino E, Gringeri A, Mannucci PM and the ReFacto-AICE Study Group. A multicenter pharmacokinetic study of the B-domain deleted recombinant factor VIII concentrate using different assays and standards. J Thromb Haemost 2003; 1: 2283±9.See also Lollar P. The factor VIII assay problem neither rhyme nor reason. This issue, pp. 2275±9.Summary. When the one-stage clotting assay is used in comparison with the chromogenic and immunological assays, plasma levels of factor (F)VIII are underestimated by 40±50% after infusion of B-domain deleted recombinant FVIII (BDD-rFVIII) in patients with hemophilia. A possible way to counteract the underestimation of FVIII levels by the one-stage assay is the adoption of a recombinant FVIII reference standard instead of a plasma standard. To evaluate the usefulness of such a standard [ReFacto 1 Laboratory Standard (RLS)], the pharmacokinetic parameters of a single dose of BDD-rFVIII (25 U kg À1 ) were evaluated in a multicenter study carried out in 18 patients with severe hemophilia A. The very low in vivo recovery, obtained with the combination of the one-stage assay and plasma reference standard, was increased up to the values obtained by the chromogenic assay when the results were expressed in terms of RLS. When the plasma standard was used, the one-stage/ chromogenic ratio was 0.82 AE 0.12 for FVIII levels above 25 U dL À1 and 1.42 AE 0.99 for FVIII levels below 25 U dL À1 . Using the RLS, the one-stage/chromogenic ratio increased to 1.01 AE 0.19 at FVIII levels above 25 U dL À1 , as a consequence of a complete overlap of the two decays; however, at FVIII levels below 25 U dL À1 , the one-stage/chromogenic ratio was still 1.6 AE 0.85. After the twelfth hour, FVIII concentrations obtained by chromogenic assay were always lower than those resulting from the one-stage clotting assay, independently of the standard used. Results obtained by chromogenic assay were not affected by the type of standard used. Compared with those obtained by the one-stage assay, higher values of clearance, lower volume of distribution area and shorter plasma half-life or mean residence time were obtained by chromogenic assay because of a shape change of the decay curve due to a shift to higher values in the ®rst part (time interval 0±12 h) and to lower values in the second part of the decay curve (time interval 12±48 h). As a consequence, the slope of the decay curve obtained by means of chromogenic assay was steeper. In conclusion, the more homogeneous results of in vivo recovery and pharmacokinetic analysis, due to the decrease of discrepancy between the two methods when RLS was used, make the cheaper and more widely used one-stage assay preferable to the more expensive chromogenic assay, on condition that the ReFacto speci®c standard has used.

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Section: Discussionmentioning

confidence: 99%

A multicenter pharmacokinetic study of the B-domain deleted recombinant factor VIII concentrate using different assays and standards

Morfini

Cinotti

Bellatreccia³

et al. 2003

Journal of Thrombosis and Haemostasis

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“…The assessment of FVIII potency of concentrates and of FVIII plasma concentration in recipients has been a matter of investigation and controversy for many years [30], and in particularly when high-purity and Mab-purified concentrates were introduced [7, [31][32][33][34]. On the other hand, longterm prophylaxis without frequent dosage adjustment may be dangerous and unsuccessful if the FVIII/ FIX level is below the trough or may be too expensive if the level is far above the minimum haemostatic level.…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics of factor VIII and factor IX

Morfini

2003

Haemophilia

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A survey of principal pharmacokinetic (PK) studies on factor VIII (FVIII) and factor IX (FIX) plasma- and rDNA-derived concentrates, analysed by means of the PKRD program, has been performed. Notwithstanding the accurate definition of the study design, released in 1991 by the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis (SSC-ISTH), a large variability of PK parameters has been pointed out. In the majority of the PK studies, the size of the population is small. In this situation, a careful individualization of haemophilia therapy is strongly recommended. The tailored prediction of loading and maintenance dosages and the need for strict control of trough FVIII/IX levels are mandatory not only to decrease the risk of bleeds but also to spare financial resources. Recently, the old problem of FVIII assay standardization has again become a concern among physicians, especially after the introduction of B-domain deleted rFVIII concentrate. The discrepancies between the widely used one-stage clotting assay and the chromogenic substrate assay seem to be solved by the introduction of a product-specific laboratory standard.

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“…Although this was broadly the case in the 1970s and early 1980s, developments in viral inactivation methods and the introduction of highpurity plasmaderived and recombinant products increased the diversity of composi tion of concentrates, and this has led to discrepancies between methods, even though concentrate standards are used [11]. Although this was broadly the case in the 1970s and early 1980s, developments in viral inactivation methods and the introduction of highpurity plasmaderived and recombinant products increased the diversity of composi tion of concentrates, and this has led to discrepancies between methods, even though concentrate standards are used [11].…”

Section: Comparison Of Methods On Concentratesmentioning

confidence: 99%