Comparison of the pharmacokinetics of two von Willebrand factor concentrates [Biostate and AHF (High Purity)] in people with von Willebrand disorder

Emmanuel J. Favaloro; John Lloyd; John Rowell; Ross Baker; Kevin Rickard; Geoff Kershaw; Alison Street; Kate Scarff; Giulio Barrese; Darryl Maher; Andrew J. McLachlan

doi:10.1160/TH06-09-0495

Thrombosis and Haemostasis, Inhaltsverzeichnis

Thromb Haemost 2007; 97(06): 922-930
DOI: 10.1160/TH06-09-0495

Blood Coagulation, Fibrinolysis and Cellular Haemostasis

Schattauer GmbH

Comparison of the pharmacokinetics of two von Willebrand factor concentrates [Biostate and AHF (High Purity)] in people with von Willebrand disorder

A randomised cross-over, multi-centre study

Emmanuel J. Favaloro

¹Haematology, Institute of Clinical Pathology and Medical Research (ICPMR), Westmead Hospital, Westmead, New South Wales, Australia

,

John Lloyd

²Haematology, Institute of Medical and Veterinary Science (IMVS), Royal Adelaide Hospital, Adelaide, South Australia, Australia

,

John Rowell

³Haematology, Royal Brisbane Hospital, Brisbane, Queensland, Australia

,

Ross Baker

⁴Haematology, Royal Perth Hospital, Perth, Western Australia, Australia

,

Kevin Rickard

⁵Haematology, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia

,

Geoff Kershaw

⁵Haematology, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia

,

Alison Street

⁶Haematology, Alfred Hospital, Melbourne, Victoria, Australia

,

Kate Scarff

⁷CSL Limited, Broadmeadows, Victoria, Australia

,

Giulio Barrese

⁷CSL Limited, Broadmeadows, Victoria, Australia

,

Darryl Maher

⁷CSL Limited, Broadmeadows, Victoria, Australia

,

Andrew J. McLachlan

⁸Faculty of Pharmacy, University of Sydney, Sydney, New South Wales, Australia

› Institutsangaben

Abstract

Summary

Plasma-derived factor concentrates are important in the management of von Willebrand disorder (VWD). In our geographic locality, a single viral inactivation step concentrate (AHF [High Purity]), has been replaced with one using a double viral inactivation step (Biostate^®). The aim of this study was to compare the pharmacokinetics of von Willebrand factor (VWF) and factor VIII (FVIII) after administration of AHF (High Purity) and Biostate^®. This study was a single-blind, randomised cross-over, multi-centre investigation in twelve people with VWD, comprising four type 3, two type 2B, one type 2M and five type 1 VWD. The subjects received a single infusion of 60 IU/kg ristocetin cofactor activity (VWF:RCo) of either AHF (High Purity) or Biostate^®, and after a minimum 15-day wash-out period they received the alternative product. Blood samples were collected for up to 48 hours after each dose for assay of FVIII coagulant activity (FVIII:C) and VWF by VWF:RCo, collagen binding capacity (VWF:CB) and antigen (VWF:Ag). As a measure of delivered VWF ‘functionality’ we calculated the area-under-the-concentration-time-curve (AUC) ratios of VWF:RCo to VWF:Ag and VWF:CB to VWF:Ag. The effect on platelet adhesiveness by PFA-100 closure times (CTs) was measured prior to and 30 minutes post infusion. VWF multimers were also assessed pre and post infusion. Pharmacokinetic parameters after AHF (High Purity) and Biostate^® were in close agreement for VWF:RCo (confirming dosing equivalence). Parameters for other study markers were also similar, although Biostate^® tended to yield relatively lower VWF:Ag and higher VWF:CB levels. Although AHF (High Purity) and Biostate^® resulted in similar levels of high-molecular-weight (HMW) multimers post-infusion, the relative level of HMW to low-molecular-weight (LMW) multimers were determined to be higher following Biostate^®. The relative levels of functional VWF (i.e. VWF:CB and VWF:RCo) to VWF:Ag were also higher in Biostate^® compared to AHF (High Purity). With both study products, PFA-100 CTs 30 minutes post infusion showed minor improvement for only some subjects. In conclusion, the pharmacokinetics of FVIII:C and VWF are not significantly different after administration of AHF (High Purity) and Biostate^®. Study parameters considered as ‘in-vitro’ markers of VWF ‘functionality’ or potential clinical efficacy (i.e. VWF:CB and VWF:RCo relative to VWF:Ag, level of HMW VWF relative to LMW-VWF) were determined to be higher for Biostate^® than AHF (High Purity). PFA-100 CTs did not adequately reflect changes in these VWF parameters. Based on these results, one would expect Biostate^® to be at least as effective, if not superior to AHF (High Purity) for the treatment of VWD.

Keywords

Pharmacokinetics - von Willebrand factor - von Willebrand disease - VWF - von Willebrand disorder - VWD - coagulation factor concentrate

Volltext

Referenzen

References
1 Sadler JE, Mannucci PM, Berntorp E. et al. Impact, diagnosis and treatment of von Willebrand disease. Thromb Haemost 2000; 84: 160-174.
2 Mannucci PM. Desmopressin (DDAVP) in the treatment of bleeding disorders: the first 20 years. Blood 1997; 90: 2515-2521.
3 Federici AB, Mazurier C, Berntorp E. et al. Biologic response to desmopressin in patients with severe type 1 and type 2 von Willebrand disease: results of a multicenter European study. Blood 2004; 103: 2032-2038.
4 United Kingdom Haemophilia Centre Doctors’ Organisation (UKHCDO) Guidelines on the selection and use of therapeutic products to treat haemophilia and other hereditary bleeding disorders. Haemophilia 2003; 9: 1-23.
5 Federici AB. Management of von Willebrand disease with factor VIII/von Willebrand factor concentrates: Results from current studies and surveys. Blood Coag Fibrinolysis 2005; 16 (Suppl. 01) S17-S21.
6 Rodeghiero F, Castaman G. Treatment of von Willebrand disease. Semin Hematol 2005; 42: 29-35.
7 Pasi KJ, Collins PW, Keeling DM. et al. Management of von Willebrand disease: A guideline from the UK Haemophilia Centre Doctor's Organization. Haemophilia 2004; 10: 218-231.
8 Castaman G, Federici AB, Rodeghiero F. et al. Von Willebrand's disease in the year 2003: Towards the complete identification of gene defects for correct diagnosis and treatment. Haematologica 2003; 88: 94-108.
9 Favaloro EJ, Bukuya M, Martinelli T. et al. A comparative multi-laboratory assessment of factor concentrate and implications for clinical efficacy as potential replacement therapy in von Willebrand’s Disease (VWD). Thromb Haemost 2002; 87: 466-476.
10 Oates A, Polmear E, Herrington R. et al. von Willebrand factor characterization of a severe dry-heat treated factor VIII concentrate, AHF (high purity). Thromb Res 1992; 65: 389-399.
11 Committee for Proprietary Medicinal Products. Guideline on the clinical investigation of human plasma derived von Willebrand factor products (CPMP/ BPWG/220/02). Nov, 2005 Available at: http://www.emea.europa.eu/pdfs/human/bpwg/022002en.pdf
12 Mannucci PM. Scientific and Standardization Committee Communication. Recommended protocol for the study of the ex vivo biological effects of virus-inactivated plasma concentrates in patients with von Willebrand disease. Thromb Haemost 1992; 68: 84-87.
13 Favaloro EJ, Grispo L, Exner T. et al. Development of a simple collagen binding assay aids in the diagnosis of, and permits sensitive discrimination between, Type I and Type II von Willebrand's disease. Blood Coagul Fibrinolysis 1991; 2: 285-291.
14 Favaloro EJ, Mehrabani PA, Koutts J. Laboratory assessment of von Willebrand factor: altered interpretation of laboratory data, and altered diagnosis of von Willebrand's disease, as influenced by the use of different vWF assays and assay conditions. Clin Appl Thromb/Hemost 1997; 3: 110-1.
15 Favaloro EJ. Collagen binding assay for von Willebrand Factor (VWF:CBA): Detection of von Willebrand’s Disease (VWD), and discrimination of VWD subtypes, depends on collagen source. Thromb Haemost 2000; 83: 127-135.
16 Favaloro EJ, Kershaw G, Bukuya M. et al. Laboratory diagnosis of von Willebrand Disorder (VWD) and monitoring of DDAVP therapy: Efficacy of the PFA-100® and VWF:CBA as combined diagnostic strategies. Haemophilia 2001; 7: 180-189.
17 Lee M, Morfini S, Schulman S. et al. and the Factor VIII/Factor IX Scientific and Standardization Committee of the International Society for Thrombosis and Haemostasis. The Design and Analysis of Pharmacokinetic Studies of Coagulation Factors. Posted on the ISTH Website, 21 March, 2001 Available at http://www.med.unc.edu/isth/SSC/communications/factor8and9/fviiipharmaco.pdf Last accessed July 19, 2006.
18 Goudemand J, Mazurier C, Marey A. et al. Clinical and biological evaluation in von Willebrand's disease of a von Willebrand factor concentrate with low factor VIII activity. Br J Haematol 1992; 80: 214-221.
19 Menache D, Aronson D, Darr F. et al. Pharmacokinetics of von Willebrand factor and factor VIIIC in patients with severe von Willebrand disease (type 3 VWD): estimation of the rate of factor VIIIC synthesis. Br J Haematol 1996; 94: 740-5.
20 Menache D. Pharmacokinetics of von Willebrand factor and FVIII coagulant activity in patients with von Willebrand disease type 2 and 3. Haemophilia 1998; 4 (Suppl. 03) 44-47.
21 Dobrkovska A, Krzensk U, Chediak JR. Pharmacokinetics, efficacy and safety of Humate-P in von Willebrand disease. Haemophilia 1998; 4 (Suppl. 03) 33-39.
22 Lubetsky A, Martinowitz U, Luboshitz J. et al. Efficacy and safety of a factor VIII-von Willebrand factor concentrate 8Y: stability, bacteriological safety, pharmacokinetic analysis and clinical experience. Haemophilia 2002; 8: 622-628.
23 Auerswald G, Eberspacher B, Engl W. et al. Successful treatment of patients with von Willebrand disease using a high-purity double-virus inactivated factor concentrate (Immunate ® ). Semin Thromb Hemost 2002; 28: 203-213.
24 Ver Elst KMM, van Vliet HDM, Kappers-Klunne MC. et al. In vitro studies, pharmacokinetic studies and clinical use of a high purity double virus inactivated FVIII/VWF concentrate (Immunate) in the treatment of von Willebrand disease. Thromb Haemost 2004; 92: 67-74.
25 Mannucci PM, Chediak J, Hanna W. et al. Alphanate Study Group. Treatment of von Willebrand disease with a high-purity factor VIII/von Willebrand factor concentrate: a prospective, multicenter study. Blood 2002; 99: 450-456.
26 Goudemand J, Scharrer I, Berntorp E. et al. Pharmacokinetic studies on Wilfactin, a von Willebrand factor concentrate with a low factor VIII content treated with three virus-inactivation/removal methods. J Thromb Haemost 2005; 3: 2219-2227.
27 Michiels JJ, Zwi N, Berneman ZN. et al. Bleeding prophylaxis for major surgery in patients with type 2 von Willebrand disease with an intermediate purity factor VIII–von Willebrand factor concentrate (Haemate- P). Blood Coagul Fibrinolysis 2004; 15: 323-330.
28 Favaloro EJ. Detection of von Willebrand disorder (VWD) and identification of qualitative von Willebrand factor (VWF) defects: Direct comparison of commercial ELISA-based ‘VWF:Activity’ options. Am J Clin Pathol 2000; 114: 608-618.
29 Favaloro EJ. von Willebrand factor (VWF) collagen binding (activity) assay (VWF:CBA) in the diagnosis of von Willebrand's disorder (VWD): A 15-year journey. Semin Thromb Hemost 2002; 28: 191-202.
30 Neugebauer BM, Goy C, Budek I. et al. Comparison of two von Willebrand factor collagen binding assays with different affinities for low, medium and high multimers of von Willebrand factor. Semin Thromb Hemost 2002; 28: 139-147.
31 Neugebauer BM, Goy C, Seitz R. A collagen binding assay: An additional method for von Willebrand factor activity in therapeutic concentrates. Thromb Haemost 2002; 88: 871-872.
32 Hubbard AR, Sands D, Chang AC. et al. Standardisation of von Willebrand factor in therapeutic concentrates: Calibration of the 1 st International Standard for von Willebrand Factor Concentrate (00/514). Thromb Haemost 2002; 88: 380-386.
33 Hubbard A. von Willebrand factor standards for plasma and concentrate testing. Semin Thromb Hemost 2006; 32: 522-527.
34 Favaloro EJ. Laboratory identification of von Willebrand disease: Technical and scientific perspectives. Semin Thromb Hemost 2006; 32: 456-471.
35 Fressinaud E, Veyradier A, Sigaud M. et al. Therapeutic monitoring of von Willebrand disease: interest and limits of a platelet function analyser at high shear rates. Br J Haematol 1999; 106: 777-783.
36 Cattaneo M, Federici AB, Lecchi A. et al. Evaluation of the PFA-100 system in the diagnosis and therapeutic monitoring of patients with von Willebrand disease. Thromb Haemost 1999; 82: 35-39.
37 Meskal A, Vertessen F, Van der Planken M. et al. The platelet function analyzer (PFA-100) may not be suitable for monitoring the therapeutic efficiency of von willebrand concentrate in type III von willebrand disease. Ann Hematol 1999; 78: 426-430.
38 Favaloro EJ. Utility of the PFA-100 ® for assessing bleeding disorders and monitoring therapy: A review of analytical variables, benefits and limitations. Haemophilia 2001; 7: 170-179.
39 Favaloro EJ. Laboratory monitoring of therapy in von Willebrand Disease: Efficacy of the PFA-100® and VWF:CB as coupled strategies. Semin Thromb Hemost 2006; 6: 566-576.
40 Menache D, Aronson DL. New treatments of von Willebrand disease: plasma derived von Willebrand factor concentrates. Thromb Haemost 1997; 78: 566-570.
41 Makris M, Colvin B, Gupta V. et al. Venous thrombosis following the use of intermediate purity concentrate to treat patients with von Willebrand disease. Thromb Haemost 2002; 88: 387-388.
42 Mannuci PM. Venous thromboembolism in von Willebrand disease. Thromb Haemost 2002; 88: 378-379.
43 Tirado I, Mateo J, Soria JM. et al. The ABO blood group genotype and factor VIII levels as independent risk factors for venous thromboembolism. Thromb Haemost 2005; 93: 468-474.
44 Wells PS, Langlois NJ, Webster MA. et al. Elevated factor VIII is a risk factor for idiopathic venous thromboembolism in Canada – is it necessary to define a new upper reference range for factor VIII?. Thromb Haemost 2005; 93: 842-846.
45 Favaloro EJ. Is elevated factor VIII a risk factor for venous thromboembolism in Canada?. Thromb Haemost 2005; 94: 1112-1113.
46 Hennan JK, Swillo RE, Morgan GA. et al. Pharmacologic inhibition of platelet vWF-GPIbα interaction prevents coronary artery thrombosis. Thromb Haemost 2006; 95: 469-475.
47 Blann AD. Plasma von Willebrand factor, thrombosis, and the endothelium: The first 30 years. Thromb Haemost 2006; 95: 49-55.
48 Mazurier C. Composition, quality control, and labeling of plasma-derived products for the treatment of von Willebrand Disease. Semin Thromb Hemost 2006; 6: 529-536.
49 Budde U, Metzner HJ, Muller H-G. Comparative analysis and classication of von Willebrand Factor/Factor VIII concentrates: Impact on treatment of patients with von Willebrand Disease. Semin Thromb Hemost 2006; 6: 626-635.