Pharmacokinetics of Beriplex P/N prothrombin complex concentrate in healthy volunteers

Helmut Ostermann; Sabine Haertel; Sigurd Knaub; Uwe Kalina; Kerstin Jung; Ingrid Pabinger

doi:10.1160/TH07-05-0367

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2007; 98(04): 790-797
DOI: 10.1160/TH07-05-0367

Blood Coagulation, Fibrinolysis and Cellular Haemostasis

Schattauer GmbH

Pharmacokinetics of Beriplex P/N prothrombin complex concentrate in healthy volunteers

Helmut Ostermann

¹University Hospital Munich – Großhadern, Medical Clinic III, Department of Haematology and Oncology, Ludwig Maximilian University, Munich, Germany

,

Sabine Haertel

²CSL Behring GmbH, Marburg, Germany

,

Sigurd Knaub

²CSL Behring GmbH, Marburg, Germany

,

Uwe Kalina

²CSL Behring GmbH, Marburg, Germany

,

Kerstin Jung

²CSL Behring GmbH, Marburg, Germany

,

Ingrid Pabinger

³Medical University Vienna, Department of Internal Medicine, Division of Clinical Haematology and Haemostaseology, Vienna, Austria

› Author Affiliations

Abstract

Summary

Prothrombin complex concentrates (PCCs) are widely administered for emergency oral anticoagulation reversal and for coagulation defects in liver disease. Pharmacokinetic data may help to optimize treatment. The objective of this study was to characterize the pharmacokinetics of a PCC (Beriplex P/N) containing coagulation factors II (FII),VII (FVII), IX (FIX) and X (FX) and anticoagulant proteins C and S. Fifteen healthy volunteers received a single rapid 50 IU/kg infusion of PCC and underwent frequent blood sampling until 144 hours (h) after infusion. Coagulation factors and anticoagulant protein pharmacokinetic parameters were estimated by non-linear regression. The mean infusion rate of PCC was 7.9 ml/min, equivalent to 196.4 IU/min. By the earliest post-infusion sampling point at 5 minutes (min), plasma FIX concentration increased by a median of 73%. Median increases in FII, FVII and FX at 5 min were 122%, 62% and 158%, respectively. Proteins C and S also increased rapidly. The median terminal half-life of FIX was 16.7 h, FII 59.7 h, FVII 4.2 h and FX 30.7 h. The median in-vivo recovery of FIX was 1.57 %/IU/kg and that of the other three coagulation factors > 2 %/IU/kg. Plasma concentration of thrombogenicity marker D-dimer did not increase, and there was no clinical evidence of thrombosis.Through up to 12 weeks follow-up there were no laboratory findings indicating PCC-related viral exposure. Rapid PCC infusion produced prompt sustained increases in coagulation factors and anticoagulant proteins with no clinical evidence of thrombosis or viral transmission.

Keywords

Prothrombin complex concentrates - pharmacokinetics - safety - blood coagulation factors - anticoagulation reversal

Full Text

References

References
1 Fihn SD, Gadisseur AA, Pasterkamp E. et al. Comparison of control and stability of oral anticoagulant therapy using acenocoumarol versus phenprocoumon.. Thromb Haemost 2003; 90: 260-266.
2 Evans G, Luddington R, Baglin T. Beriplex P/N reverses severe warfarin-induced overanticoagulation immediately and completely in patients presenting with major bleeding.. Br J Haematol 2001; 115: 998-1001.
3 Preston FE, Laidlaw ST, Sampson B. et al. Rapid reversal of oral anticoagulation with warfarin by a prothrombin complex concentrate (Beriplex): efficacy and safety in 42 patients.. Br J Haematol 2002; 116: 619-624.
4 Huttner HB, Schellinger PD, Hartmann M. et al. Hematoma growth and outcome in treated neurocritical care patients with intracerebral hemorrhage related to oral anticoagulant therapy: comparison of acute treatment strategies using vitamin K, fresh frozen plasma, and prothrombin complex concentrates.. Stroke 2006; 37: 1465-1470.
5 Lorenz R, Kienast J, Otto U. et al. Successful emergency reversal of phenprocoumon anticoagulation with prothrombin complex concentrate: A prospective clinical study.. Blood Coagul Fibrinolysis 2007; 18: 565-570.
6 Schulman S. Care of patients receiving long-term anticoagulant therapy.. N Engl J Med 2003; 349: 675-683.
7 O’Shaughnessy DF, Atterbury C, Bolton Maggs P. et al. Guidelines for the use of fresh-frozen plasma, cryoprecipitate and cryosupernatant.. Br J Haematol 2004; 126: 11-28.
8 Makris M. Optimisation of the prothrombin complex concentrate dose for warfarin reversal.. Thromb Res 2005; 115: 451-453.
9 Baglin TP, Keeling DM, Watson HG. Guidelines on oral anticoagulation (warfarin): third edition – 2005 update.. Br J Haematol 2006; 132: 277-285.
10 Dentali F, Ageno W, Crowther M. Treatment of coumarin- associated coagulopathy: a systematic review and proposed treatment algorithms.. J Thromb Haemost 2006; 4: 1853-1863.
11 Schulman S, Bijsterveld NR. Anticoagulants and their reversal.. Transfus Med Rev 2007; 21: 37-48.
12 Yasaka M, Minematsu K, Naritomi H. et al. Predisposing factors for enlargement of intracerebral hemorrhage in patients treated with warfarin.. Thromb Haemost 2003; 89: 278-283.
13 Gasse C, Hollowell J, Meier CR. et al. Drug interactions and risk of acute bleeding leading to hospitalisation or death in patients with chronic atrial fibrillation treated with warfarin.. Thromb Haemost 2005; 94: 537-543.
14 Kim HC, McMillan CW, White GC. et al. Purified factor IX using monoclonal immunoaffinity technique: clinical trials in hemophilia B and comparison to prothrombin complex concentrates.. Blood 1992; 79: 568-575.
15 Berntorp E, Björkman S, Carlsson M. et al. Biochemical and in vivo properties of high purity factor IX concentrates.. Thromb Haemost 1993; 70: 768-773.
16 Björkman S, Carlsson M, Berntorp E. Pharmacokinetics of factor IX in patients with haemophilia B. Methodological aspects and physiological interpretation.. Eur J Clin Pharmacol 1994; 46: 325-332.
17 Poon MC, Aledort LM, Anderle K. et al. Comparison of the recovery and half-life of a high-purity factor IX concentrate with those of a factor IX complex concentrate. Factor IX Study Group.. Transfusion 1995; 35: 319-323.
18 Ruiz-Sáez A, Hong A, Arguello A. et al. Pharmacokinetics, thrombogenicity and safety of a double viral inactivated factor IX concentrate compared with a prothrombin complex concentrate.. Haemophilia 2005; 11: 583-588.
19 Shapiro AD, Korth-Bradley J, Poon MC. Use of pharmacokinetics in the coagulation factor treatment of patients with haemophilia.. Haemophilia 2005; 11: 571-582.
20 Poon MC. Pharmacokinetics of factors IX, recombinant human activated factor VII and factor XIII.. Haemophilia 2006; 12 (Suppl. 04) 61-69.
21 Longo G, Cinotti S, Filimberti E. et al. Single-dose pharmacokinetics of factor IX evaluated by model-independent methods.. Eur J Haematol 1987; 39: 426-433.
22 Morfini M, Longo G, Berntorp E. et al. Pharmacokinetics, thrombogenicity and safety of a doubletreated prothrombin complex concentrate.. Thromb Res 1993; 71: 175-184.
23 Smith KJ, Thompson AR. Labeled factor IX kinetics in patients with hemophilia-B.. Blood 1981; 58: 625-629.
24 Okajima K, Koga S, Kaji M. et al. Effect of protein C and activated protein C on coagulation and fibrinolysis in normal human subjects.. Thromb Haemost 1990; 63: 48-53.
25 Riess H, Binsack T, Hiller E. Protein C antigen in prothrombin complex concentrates: content, recovery and half life.. Blut 1985; 50: 303-306.
26 Griffin JH. Clinical studies of protein C.. Semin Thromb Hemost 1984; 10: 162-166.
27 Vukovich T, Auberger K, Weil J. et al. Replacement therapy for a homozygous protein C deficiency-state using a concentrate of human protein C and S.. Br J Haematol 1988; 70: 435-440.
28 Auberger K. Evaluation of a new protein-C concentrate and comparison of protein-C assays in a child with congenital protein-C deficiency.. Ann Hematol 1992; 64: 146-151.
29 Baliga V, Thwaites R, Tillyer ML. et al. Homozygous protein C deficiency—management with protein C concentrate.. Eur J Pediatr 1995; 154: 534-538.
30 de Kleijn ED, de Groot R, Hack CE. et al. Activation of protein C following infusion of protein C concentrate in children with severe meningococcal sepsis and purpura fulminans: a randomized, double-blinded, placebo-controlled, dose-finding study.. Crit Care Med 2003; 31: 1839-1847.
31 D’Angelo A, Vigano-D’Angelo S, Esmon CT. et al. Acquired deficiencies of protein S. Protein S activity during oral anticoagulation, in liver disease, and in disseminated intravascular coagulation.. J Clin Invest 1988; 81: 1445-1454.
32 D’Angelo A, Della Valle P, Crippa L. et al. Relationship between international normalized ratio values, vitamin K-dependent clotting factor levels and in vivo prothrombin activation during the early and steady phases of oral anticoagulant treatment.. Haematologica 2002; 87: 1074-1080.
33 Köhler M. Thrombogenicity of prothrombin complex concentrates.. Thromb Res 1999; 95: S13-17.
34 Staudinger T, Frass M, Rintelen C. et al. Influence of prothrombin complex concentrates on plasma coagulationin critically ill patients.. Intensive Care Med 1999; 25: 1105-1110.
35 Lorenz R, Kienast J, Otto U. et al. Efficacy and safety of a prothrombin complex concentrate with two virus-inactivation steps in patients with severe liver damage.. Eur J Gastroenterol Hepatol 2003; 15: 15-20.
36 Rodewald L, Scharrer I. Protein chemical investigation of 30 consecutive lots of double-virus eliminated PCC (Beriplex P/N) and summary of safety data.. Hämostaseologie 2004; 24: A46.
37 Cherian G, Nokes TJC. A snapshot of the use of Beriplex P/N within a large tertiary hospital.. Br J Haematol 2005; 129 (Suppl. 01) 74.
38 Mannucci PM, Giangrande PL. Detection of the prethrombotic state due to procoagulant imbalance.. Eur J Haematol 1992; 48: 65-69.
39 Bauer KA, Rosenberg RD. The pathophysiology of the prethrombotic state in humans: insights gained from studies using markers of hemostatic system activation.. Blood 1987; 70: 343-350.
40 Mannucci PM, Bauer KA, Gringeri A. et al. Thrombin generation is not increased in the blood of hemophilia B patients after the infusion of a purified factor IX concentrate.. Blood 1990; 76: 2540-2545.
41 Mannucci PM, Bauer KA, Gringeri A. et al. No activation of the common pathway of the coagulation cascade after a highly purified factor IX concentrate.. Br J Haematol 1991; 79: 606-611.
42 Santagostino E, Mannucci PM, Gringeri A. et al. Markers of hypercoagulability in patients with hemophilia B given repeated, large doses of factor IX concentrates during and after surgery.. Thromb Haemost 1994; 71: 737-740.
43 Thomas DP, Hampton KK, Dasani H. et al. A cross-over pharmacokinetic and thrombogenicity study of a prothrombin complex concentrate and a purified factor IX concentrate.. Br J Haematol 1994; 87: 782-788.
44 Philippou H, Adami A, Lane DA. et al. High purity factor IX and prothrombin complex concentrate (PCC): pharmacokinetics and evidence that factor IXa is the thrombogenic trigger in PCC.. Thromb Haemost 1996; 76: 23-28.
45 Retzlaff JA, Tauxe WN, Kiely JM. et al. Erythrocyte volume, plasma volume, and lean body mass in adult men and women.. Blood 1969; 33: 649-661.
46 Lubetsky A, Hoffman R, Zimlichman R. et al. Efficacy and safety of a prothrombin complex concentrate (Octaplex) for rapid reversal of oral anticoagulation.. Thromb Res 2004; 113: 371-378.
47 Römisch J, Gröner A, Bernhardt D. et al. Nanofiltration bei der Herstellung von Beriplex® P/N: Erhöhung der Kapazität zur Viruseliminierung unter Beibehaltung der Produktqualität.. Beitr Infusionsther Transfusionsmed 1996; 33: 220-224.
48 Weimer T, Streichert S, Watson C. et al. High-titer screening PCR: a successful strategy for reducing the parvovirus B19 load in plasma pools for fractionation.. Transfusion 2001; 41: 1500-1504.
49 Chandra S, Groener A, Feldman F. Effectiveness of alternative treatments for reducing potential viral contaminants from plasma-derived products.. Thromb Res 2002; 105: 391-400.
50 van Aart L, Eijkhout HW, Kamphuis JS. et al. Individualized dosing regimen for prothrombin complex concentrate more effective than standard treatment in the reversal of oral anticoagulant therapy: An open, prospective randomized controlled trial.. Thromb Res 2006; 118: 313-320.