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Factor VIII (FVIII) and factor IX (FIX) have unique pharmacokinetic (PK) profiles and behave differently in the body. They have differences in half-life, clearance, recovery and volume of distribution1–5
Volume of distribution describes the relationship between the amount of a drug in the body and its plasma concentration6
FVIII and FIX distribute differently—FVIII primarily remains in the plasma (Fig.1), whereas FIX rapidly distributes outside of the plasma and binds to type IV collagen within the extravascular space, reducing its plasma concentration (Fig. 2).1–5,7
Volume of distribution (VD) describes the relationship between the amount of drug in the body and the plasma drug concentration (mL/kg). Drugs with a high volume of distribution will have lower trough levels.6
FVIII has a VD close to the normal blood plasma volume (40–41 mL/kg), i.e. it stays primarily in plasma1,8
FIX extravascular distribution and binding to type IV collagen is not quantifiable in clinical practice for patients receiving FIX replacement therapy2,9
Although clinical trials have not directly compared extended half-life factor IX (EHL-FIX) products, the individual trials have shown a broad range of trough levels and a narrow range of bleed rates10-12
Recent data by Malec et al. characterised the use and performance of EHL-FIX concentrates in clinical practice: rFIX-Fc, rFIX-FP and rFIX-GP.14
Real-world performance was characterised using a survey of patients with severe haemophilia B across six centres in the US and Canada14
A wide range of volumes of distribution are reported among extended half-life EHL-FIX products*16-18
The volume of distribution for some EHL-FIX concentrates is substantially higher than the estimated plasma volume of 40 mL/kg1
*The volume of distribution of rFIXFc is 303 ml/kg.16 Geometric mean, based on single PK dose of 50 IU/kg.16 The volume of distribution of rIX-FP is 102 ml/kg.17 Arithmetic mean, based on single PK dose of 50 IU/kg.17 The volume of distribution of N9-GP is 47 ml/kg.18 Geometric mean, based on single PK dose of 40 IU/kg.18
Besides bleed protection, many adult patients with haemophilia B report other physical and psychological needs that are not fully managed20
World Federation of Hemophilia (WFH) guidelines identify prevention of bleeds, preservation of joint health, prevention of inhibitor development, and improved patient quality of life as key therapeutic goals19
Iorio A, Fischer K, Blanchette V, et al. Tailoring treatment of haemophilia B: accounting for the distribution and clearance of standard and extended half-life FIX concentrates. Thromb Haemostat 2017;117(6):1023–30.
Gui T, Lin HF, Hoffman M, et al. Circulating and binding characteristics of wild-type factor IX and certain Gla domain mutants in vivo. Blood 2002;100(1):153–8.
Lenting PJ, van Schooten CJ, Denis CV. Clearance mechanisms of von Willebrand factor and factor VIII. J Thromb Haemost 2007;5(7):1353–60.
Morfini M. The History of Clotting Factor Concentrates Pharmacokinetics. J Clin Med 2017;6(3):35.
Feng D, Stafford KA, Broze GJ, Stafford DW. Evidence of clinically significant extravascular stores of factor IX. J Thromb Haemost 2013;11(12):2176–78.
McNamara PJ, Leggas M. Drug distribution. In: Hacker M, Messer W, Bachmann K, eds. Pharmacology: Principles and Practice. Burlington, MA: Elsevier Academic Press; 2009:113–127.
Nazeef M, JP Sheehan. New developments in the management of moderate-to-severe haemophilia B. J Blood Med 2016;7:27–38.
Berntorp E, Björkman S. The pharmacokinetics of clotting factor therapy. Haemophilia 2003;9:353–59.
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;46:325–32.
Powell JS, Pasi JK, Ragni MV, et al. Phase 3 Study of Recombinant Factor IX Fc Fusion Protein in Hemophilia B. N Engl J Med 2013; 369:2313–23.
Collins PW, Young G, Karim FA, et al. Recombinant long-acting glycoPEGylated factor IX in hemophilia B: a multinational randomized phase 3 trial. Blood 2014;124(26):3880–86.
Santagostino E, Martinowitz U, Lissitchkov T, et al. Long-acting recombinant coagulation factor IX albumin fusion protein (rIX-FP) in hemophilia B: results of a phase 3 trial. Blood 2016;127(14):1761–69.
Diao L, Li S, Ludden T, et al. Population pharmacokinetic modelling of recombinant factor IX Fc fusion protein (rFIXFc) in patients with haemophilia B. Clin Pharmacokinet 2014;53(5):467–77.
Malec LM, Croteau SE, Callaghan M, et al. Spontaneous Bleeding and Poor Bleeding Response with Extended Half-Life Factor IX Products: A Survey of Select US and Canadian Hemophilia Treatment Centers. Presented at ASH Annual Meeting, 8 December 2019, Orlando, Florida. Abstract 2407.
Salas J, van der Flier A, Hong V, et al. Extravascular distribution of conventional and EHL FIX products using in vivo SPECT imaging analysis in hemophilia B mice. Presented at ASH Annual Meeting, 9–12 December 2017, Atlanta, GA, USA. Poster P1061.
ALPROLIX Summary of Product Characteristics. Available from: https://www.ema.europa.eu/en/documents/product-information/alprolix-epar-product-information_en.pdf. Accessed: April 2020.
Idelvion USPI. Available from: https://www.fda.gov/media/96526/download. Accessed February 2020.
Refixia Summary of Product Characteristics. Available from: https://www.ema.europa.eu/en/documents/product-information/refixia-epar-product-information_en.pdf. Accessed: April 2020
Srivastava A, Brewer AK, Mauser-Bunschoten EP, et al. Guidelines for the management of hemophilia. Haemophilia 2013;19: e1–e47.
Yang K, Weston S, Schneider B, et al. “What Matters Most in Hemophilia” – A Quantitative Survey of People Living with or Caring for Someone with Hemophilia. [ISPOR Abstract]. Value in Health 2017; 20:A236.