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Clinical Pharmacokinetics
Published in: Clinical Pharmacokinetics 9/2017

Open Access 01-09-2017 | Original Research Article

Improved Pharmacokinetics with BAY 81-8973 Versus Antihemophilic Factor (Recombinant) Plasma/Albumin-Free Method: A Randomized Pharmacokinetic Study in Patients with Severe Hemophilia A

Authors: Anita Shah, Alexander Solms, Dirk Garmann, Yvonne Katterle, Verzhiniya Avramova, Stanislav Simeonov, Toshko Lissitchkov

Published in: Clinical Pharmacokinetics | Issue 9/2017

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Abstract

Background

BAY 81-8973 is a full-length, unmodified, recombinant human factor VIII (FVIII) for the treatment of hemophilia A.

Objective

The aim of this study was to compare the pharmacokinetic (PK) profile of BAY 81-8973 with antihemophilic factor (recombinant) plasma/albumin-free method (rAHF-PFM)

Patients/Methods

In this phase I, open-label, crossover study, men aged 18–65 years with severe hemophilia A and ≥150 exposure days to FVIII were randomized to receive a single intravenous infusion of 50 IU/kg BAY 81-8973 or rAHF-PFM, followed by crossover to a single infusion of the other treatment. FVIII levels were measured in plasma over 48 h using one-stage and chromogenic assays. PK parameters, including area under the curve from time zero to the last data point (AUClast; primary outcome) and half-life (t ½) were calculated. A population PK model was developed to simulate various treatment scenarios.

Results

Eighteen patients were randomized and analyzed. Using both assays, geometric mean (coefficient of variation [%CV]) AUClast was significantly higher, and t ½ was significantly longer, for BAY 81-8973 versus rAHF-PFM (one-stage, AUClast: 1660 IU·h/dL [29.4] vs. 1310 IU·h/dL [29.0], p < 0.0001; one-stage, t ½: 14.5 [25.7] vs. 11.7 h [27.3], p < 0.0001). Simulations showed that median time to 1 IU/dL was approximately 27% longer for BAY 81-8973 versus rAHF-PFM over doses of 25–50 IU/kg; plasma levels >1 IU/dL could be maintained with 14.4 IU/kg BAY 81-8973 or 39.1 IU/kg rAHF-PFM 3×/week.

Conclusions

BAY 81-8973 showed a superior PK profile versus rAHF-PFM. The same FVIII trough threshold level could be achieved with lower doses of BAY 81-8973 versus rAHF-PFM.
ClinicalTrials.gov: NCT02483208.
Literature
1.
Srivastava A, Brewer AK, Mauser-Bunschoten EP, et al. Guidelines for the management of hemophilia. Haemophilia. 2013;19(1):e1–47.CrossRefPubMed
2.
3.
Pavlova A, Oldenburg J. Defining severity of hemophilia: more than factor levels. Semin Thromb Hemost. 2013;39(7):702–10.CrossRefPubMed
4.
Rendo P, Shafer F, Korth-Bradley JM, et al. Factors that influence the bleeding phenotype in severe hemophilic patients. Blood Coagul Fibrinolysis. 2013;24(7):683–90.CrossRefPubMed
5.
Valentino LA. Considerations in individualizing prophylaxis in patients with haemophilia A. Haemophilia. 2014;20(5):607–15.CrossRefPubMed
6.
7.
Ahnstrom J, Berntorp E, Lindvall K, et al. A 6-year follow-up of dosing, coagulation factor levels and bleedings in relation to joint status in the prophylactic treatment of haemophilia. Haemophilia. 2004;10(6):689–97.CrossRefPubMed
8.
Collins PW, Blanchette VS, Fischer K, et al. Break-through bleeding in relation to predicted factor VIII levels in patients receiving prophylactic treatment for severe hemophilia A. J Thromb Haemost. 2009;7(3):413–20.CrossRefPubMed
9.
Shah A, Delesen H, Garger S, et al. Pharmacokinetic properties of BAY 81-8973, a full-length recombinant factor VIII. Haemophilia. 2015;21(6):766–71.CrossRefPubMed
10.
Bovenschen N, Rijken DC, Havekes LM, et al. The B domain of coagulation factor VIII interacts with the asialoglycoprotein receptor. J Thromb Haemost. 2005;3(6):1257–65.CrossRefPubMed
11.
Saxena K, Lalezari S, Oldenberg J, et al. Efficacy and safety of BAY 81-8973, a full-length recombinant factor VIII: results from the LEOPOLD I trial. Haemophilia. 2016;22(5):706–12.CrossRefPubMed
12.
Kavakli K, Yang R, Rusen L, et al. Prophylaxis versus on-demand treatment with BAY 81-8973, a full-length plasma-protein–free rFVIII product: results from a randomized trial (LEOPOLD II). J Thromb Haemost. 2015;13(3):360–9.CrossRefPubMedPubMedCentral
13.
Ljung R, Kenet G, Mancuso ME, et al. BAY 81-8973 safety and efficacy for prophylaxis and treatment of bleeds in previously treated children with severe haemophilia A: results of the LEOPOLD Kids Trial. Haemophilia. 2016;22(3):354–60.CrossRefPubMed
14.
Lissitchkov T, Tiede A, Valentino L, et al. Pharmacokinetics and efficacy of on-demand treatment with human-cl rhFVIII in previously treated patients with severe hemophilia A [abstract]. Haemophilia. 2012;18(Suppl 3):150.
15.
Jimenez-Yuste V, Lejniece S, Klamroth R, et al. The pharmacokinetics of a B-domain truncated recombinant factor VIII, turoctocog alfa (NovoEight®), in patients with hemophilia A. J Thromb Haemost. 2015;13(3):370–9.CrossRefPubMed
16.
Konkle BA, Stasyshyn O, Chowdary P, et al. Pegylated, full-length, recombinant factor VIII for prophylactic and on-demand treatment of severe hemophilia A. Blood. 2015;126(9):1078–85.CrossRefPubMedPubMedCentral
17.
Klamroth R, Simpson M, von Depka-Prondzinski M, et al. Comparative pharmacokinetics of rVIII-single chain and octocog alfa (Advate®) in patients with severe haemophilia A. Haemophilia. 2016;22(5):730–8.CrossRefPubMed
18.
Bjorkman S, Oh M, Spotts G, et al. Population pharmacokinetics of recombinant factor VIII: the relationships of pharmacokinetics to age and body weight. Blood. 2012;119(2):612–8.CrossRefPubMed
19.
Kogenate® FS (antihemophilic factor [recombinant] formulated with sucrose). Full prescribing information. Whippany: Bayer; 2015.
20.
Coyle TE, Reding MT, Lin JC, et al. Phase I study of BAY 94-9027, a PEGylated B-domain-deleted recombinant factor VIII with an extended half-life, in subjects with hemophilia A. J Thromb Haemost. 2014;12(4):488–96.CrossRefPubMedPubMedCentral
21.
Powell JS, Josephson NC, Quon D, et al. Safety and prolonged activity of recombinant factor VIII Fc fusion protein in hemophilia A patients. Blood. 2012;119(13):3031–7.CrossRefPubMedPubMedCentral
22.
Valentino LA, Mamonov V, Hellmann A, et al. A randomized comparison of two prophylaxis regimens and a paired comparison of on-demand and prophylaxis treatments in hemophilia A management. J Thromb Haemost. 2012;10(3):359–67.CrossRefPubMedPubMedCentral
23.
Tarantino MD, Collins PW, Hay CR, et al. Clinical evaluation of an advanced category antihaemophilic factor prepared using a plasma/albumin-free method: pharmacokinetics, efficacy, and safety in previously treated patients with haemophilia A. Haemophilia. 2004;10(5):428–37.CrossRefPubMed
24.
Advate® (antihemophilic factor [recombinant] plasma/albumin-free method). Full prescribing information. Westlake Village: Baxter Healthcare Corporation; 2014.
25.
Lalezari S, Martinowitz U, Windyga J, et al. Correlation between endogenous VWF: Ag and PK parameters and bleeding frequency in severe haemophilia A subjects during three-times-weekly prophylaxis with rFVIII-FS. Haemophilia. 2014;20(1):e15–22.CrossRefPubMed
26.
Di Paola J, Smith MP, Klamroth R, et al. ReFacto and Advate: a single-dose, randomized, two-period crossover pharmacokinetics study in subjects with haemophilia A. Haemophilia. 2007;13(2):124–30.CrossRefPubMed
27.
Martinowitz U, Bjerre J, Brand B, et al. Bioequivalence between two serum-free recombinant factor VIII preparations (N8 and ADVATE®)–n open-label, sequential dosing pharmacokinetic study in patients with severe haemophilia A. Haemophilia. 2011;17(6):854–9.CrossRefPubMed
28.
Collins PW, Fischer K, Morfini M, et al. Implications of coagulation factor VIII and IX pharmacokinetics in the prophylactic treatment of haemophilia. Haemophilia. 2011;17(1):2–10.CrossRefPubMed
29.
Jayandharan GR, Srivastava A. The phenotypic heterogeneity of severe hemophilia. Semin Thromb Hemost. 2008;34(1):128–41.CrossRefPubMed
30.
Mahdi AJ, Obaji SG, Collins PW. Role of enhanced half-life factor VIII and IX in the treatment of haemophilia. Br J Haematol. 2015;169(6):768–76.CrossRefPubMed
31.
Collins PW, Bjorkman S, Fischer K, et al. Factor VIII requirement to maintain a target plasma level in the prophylactic treatment of severe hemophilia A: influences of variance in pharmacokinetics and treatment regimens. J Thromb Haemost. 2010;8(2):269–75.CrossRefPubMed
Metadata
Title
Improved Pharmacokinetics with BAY 81-8973 Versus Antihemophilic Factor (Recombinant) Plasma/Albumin-Free Method: A Randomized Pharmacokinetic Study in Patients with Severe Hemophilia A
Authors
Anita Shah
Alexander Solms
Dirk Garmann
Yvonne Katterle
Verzhiniya Avramova
Stanislav Simeonov
Toshko Lissitchkov
Publication date
01-09-2017
Publisher
Springer International Publishing
Published in
Clinical Pharmacokinetics / Issue 9/2017
Print ISSN: 0312-5963
Electronic ISSN: 1179-1926
DOI
https://doi.org/10.1007/s40262-016-0492-2

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