Thromb Haemost 2017; 117(06): 1023-1030
DOI: 10.1160/TH16-12-0942
Review Article
Schattauer GmbH

Tailoring treatment of haemophilia B: accounting for the distribution and clearance of standard and extended half-life FIX concentrates

Alfonso Iorio
1   Department of Health Research Methods, Evidence, and Impact and Department of Medicine, McMaster University, Hamilton, Ontario, Canada
,
Kathelijn Fischer
2   Van Creveldkliniek, University Medical Center, Utrecht, The Netherlands
,
Victor Blanchette
3   Division of Hematology/Oncology, Hospital for Sick Children and Department of Pediatrics, University of Toronto, Toronto, Ontario, Canada
,
Savita Rangarajan
4   Haemophilia, Haemostasis & Thrombosis Centre Hampshire Hospitals NHS Foundation Trust, Basingstoke, UK
,
Guy Young
5   Children’s Hospital Los Angeles, Keck School of Medicine, University of Southern California, California, USA
,
Massimo Morfini
6   Italian Association of Haemophilia Centres (AICE), Florence, Italy
,
for the Pharmacokinetic (PK) Expert Working Group of the International Prophylaxis Study Group (the IPSG) › Author Affiliations
Further Information

Publication History

Received: 18 December 2016

Accepted after major revision: 08 March 2017

Publication Date:
07 November 2017 (online)

Summary

The prophylactic administration of factor IX (FIX) is considered the most effective treatment for haemophilia B. The inter-individual variability and complexity of the pharmacokinetics (PK) of FIX, and the rarity of the disease have hampered identification of an optimal treatment regimens. The recent introduction of extended half-life recombinant FIX molecules (EHL-rFIX), has prompted a thorough reassessment of the clinical efficacy, PK and pharmacodynamics of plasma-derived and recombinant FIX. First, using longer sampling times and multi-compartmental PK models has led to more precise (and favourable) PK for FIX than was appreciated in the past. Second, investigating the distribution of FIX in the body beyond the vascular space (which is implied by its complex kinetics) has opened a new research field on the role for extravascular FIX. Third, measuring plasma levels of EHL-rFIX has shown that different aPTT reagents have different accuracy in measuring different FIX molecules. How will this new knowledge reflect on clinical practice? Clinical decision making in haemophilia B requires some caution and expertise. First, comparisons between different FIX molecules must be assessed taking into consideration the comparability of the populations studied and the PK models used. Second, individual PK estimates must rely on multi-compartmental models, and would benefit from adopting a population PK approach. Optimal sampling times need to be adapted to the prolonged half-life of the new EHL FIX products. Finally, costs considerations may apply, which is beyond the scope of this manuscript but might be deeply connected with the PK considerations discussed in this communication.

Supplementary Material to this article is available online at www.thrombosis-online.com.

 
  • References

  • 1 Tagariello G, Iorio A, Santagostino E. et al. Comparison of the rates of joint arthroplasty in patients with severe factor VIII and IX deficiency: an index of different clinical severity of the 2 coagulation disorders. Blood 2009; 114: 779-784.
  • 2 Mannucci PM, Franchini M. Is haemophilia B less severe than haemophilia A?. Haemophilia 2013; 19: 499-502.
  • 3 Santagostino E, Fasulo M. Haemophilia A and Haemophilia B: Different Types of Diseases?. Semin Thromb Hemost 2013; 39: 697-701.
  • 4 Melchiorre D, Linari S, Manetti M. et al. Clinical, instrumental, serological and histological findings suggest that haemophilia B may be less severe than haemophilia A. Haematologica 2016; 101: 219-225.
  • 5 Clausen N, Petrini P, Claeyssens-Donadel S. et al. Similar bleeding phenotype in young children with haemophilia A or B: a cohort study. Haemophilia 2014; 20: 747-755.
  • 6 Iorio A, Marchesini E, Marcucci M. et al. Clotting factor concentrates given to prevent bleeding and bleeding-related complications in people with haemophilia A or B. Cochrane Database Syst Rev 2011; 9: CD003429.
  • 7 Traore AN, Chan AKC, Webert KE. et al. First analysis of 10-year trends in national factor concentrates usage in haemophilia: data from CHARMS, the Canadian Haemophilia Assessment and Resource Management System. Haemophilia 2014; 20: e251-259.
  • 8 Roth DA, Kessler CM, Pasi KJ. et al. Human recombinant factor IX: safety and efficacy studies in haemophilia B patients previously treated with plasma-derived factor IX concentrates. Blood 2001; 98: 3600-3606.
  • 9 Shapiro AD. The safety and efficacy of recombinant human blood coagulation factor IX in previously untreated patients with severe or moderately severe haemophilia B. Blood 2005; 105: 518-525.
  • 10 Lambert T, Recht M, Valentino L a. et al. Reformulated BeneFix: efficacy and safety in previously treated patients with moderately severe to severe haemophilia B. Haemophilia 2007; 13: 233-243.
  • 11 Shapiro AD, Ragni M V, Valentino L a. et al. Recombinant factor IX-Fc fusion protein (rFIXFc) demonstrates safety and prolonged activity in a phase 1/2a study in haemophilia B patients. Blood 2012; 119: 666-672.
  • 12 Santagostino E, Negrier C, Klamroth R. et al. Safety and pharmacokinetics of a novel recombinant fusion protein linking coagulation factor IX with albumin (rIX-FP) in haemophilia B patients. Blood 2012; 120: 2405-2411.
  • 13 Negrier C, Knobe K, Tiede A. et al. Enhanced pharmacokinetic properties of a glycoPEGylated recombinant factor IX: a first human dose trial in patients with haemophilia B. Blood 2011; 118: 2695-2701.
  • 14 Ljung R, Andersson NG, Gretenkort Andersson N. The current status of prophylactic replacement therapy in children and adults with haemophilia. Br J Haematol 2015; 169: 777-786.
  • 15 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: 768-776.
  • 16 Powell J, Shapiro A, Ragni M. et al. Switching to recombinant factor IX Fc fusion protein prophylaxis results in fewer infusions, decreased factor IX consumption and lower bleeding rates. Br J Haematol 2014; 168: 113-123.
  • 17 Wyrwich KW, Krishnan S, Auguste P. et al. Changes in health-related quality of life with treatment of longer-acting clotting factors: results in the A-LONG and B-LONG clinical studies. Haemophilia. 2016 Epub ahead of print.
  • 18 Négrier C, Abdul Karim F, Lepatan LM. et al. Efficacy and safety of long-acting recombinant fusion protein linking factor IX with albumin in haemophilia B patients undergoing surgery. Haemophilia 2016; 22: e259-266.
  • 19 Young G, Collins PW, Colberg T. et al. Nonacog beta pegol (N9-GP) in haemophilia B: A multinational phase III safety and efficacy extension trial (paradigmTM4). Thromb Res 2016; 141: 69-76.
  • 20 Escobar MA, Tehranchi R, Karim FA. et al. Low-factor consumption for major surgery in haemophilia B with long-acting recombinant glycoPEGylated factor IX. Haemophilia 2016; 1-10.
  • 21 Powell J, Shapiro A, Ragni M. et al. Switching to recombinant factor IX Fc fusion protein prophylaxis results in fewer infusions, decreased factor IX consumption and lower bleeding rates. Br J Haematol 2015; 168: 113-123.
  • 22 Hubbard AR. Potency labelling of novel factor VIII and factor IX concentrates: past experience and current strategy. Semin Thromb Hemost 2015; 41: 849-854.
  • 23 Dodt J, Hubbard AR, Wicks SJ. et al. Potency determination of factor VIII and factor IX for new product labelling and postinfusion testing: challenges for care-givers and regulators. Haemophilia 2015; 21: 543-549.
  • 24 Wilmot H V, Hogwood J, Gray E. Recombinant factor IX: discrepancies between one-stage clotting and chromogenic assays. Haemophilia 2014; 20: 891-897.
  • 25 Sommer JM, Buyue Y, Bardan S. et al. Comparative field study: impact of laboratory assay variability on the assessment of recombinant factor IX Fc fusion protein (rFIXFc) activity. Thromb Haemost 2014; 112: 932-940.
  • 26 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.
  • 27 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.
  • 28 Björkman S, Shapiro AD, Berntorp E. Pharmacokinetics of recombinant factor IX in relation to age of the patient: implications for dosing in prophylaxis. Haemophilia 2001; 7: 133-139.
  • 29 Carlsson M, Björkman S, Berntorp E. Multidose pharmacokinetics of factor IX: implications for dosing in prophylaxis. Haemophilia 1998; 4: 83-88.
  • 30 Kisker CT, Eisberg A, Schwartz B. et al. Prophylaxis in factor IX deficiency product and patient variation. Haemophilia 2003; 9: 279-284.
  • 31 Rocca A, Pizzinelli S, Oliovecchio E. et al. Replacement therapy with recombinant factor IX. A multicentre evaluation of current dosing practices in Italy. Blood Transfus 2010; 9: 60-69.
  • 32 Turecek PL, Abbühl B, Tangada SD. et al. Nonacog gamma, a novel recombinant factor IX with low factor IXa content for treatment and prophylaxis of bleeding episodes. Expert Rev Clin Pharmacol 2015; 8: 163-177.
  • 33 Windyga J, Lin VW, Epstein JD. et al. Improvement in health-related quality of life with recombinant factor IX prophylaxis in severe or moderately severe haemophilia B patients: results from the BAX326 Pivotal Study. Haemophilia 2014; 20: 362-368.
  • 34 Hay CRM. Purchasing factor concentrates in the 21st century through competitive tendering. Haemophilia 2013; 19: 660-667.
  • 35 Valentino L a, Rusen L, Elezovic I. et al. Multicentre, randomized, open-label study of on-demand treatment with two prophylaxis regimens of recombinant coagulation factor IX in haemophilia B subjects. Haemophilia 2014; 20: 398-406.
  • 36 Cooley B. Prophylactic efficacy of BeneFIX vs Alprolix in haemophilia B mice. Blood 2016; 126: 286-292.
  • 37 Morfini M, Lee M, Messori A. The design and analysis of half-life and recovery studies for factor VIII and factor IX. Factor VIII/Factor IX Scientific and Stan-dardisation Committee of the International Society for Thrombosis and Haemostasis. Thromb Haemost 1991; 66: 384-386.
  • 38 FDA. Guidance for Industry Use in Medical Product Development to Support Labelling Claims Guidance for Industry. 2009; 1-39.
  • 39 EMA. Guideline on clinical investigation of recombinant and human plasma-derived factor IX products. 2011
  • 40 Björkman S. Pharmacokinetics of plasma-derived and recombinant factor IX – implications for prophylaxis and on-demand therapy. Haemophilia 2013; 19: 808-813.
  • 41 Morfini M, Dragani A, Paladino E. et al. Correlation between FIX genotype and pharmacokinetics of Nonacog alpha according to a multicentre Italian study. Haemophilia. 2016 Epub ahead of print.
  • 42 Brekkan A, Berntorp E, Jensen K. et al. Population pharmacokinetics of plasma-derived factor IX: procedures for dose individualisation. J Thromb Haemost 2016; 14: 724-732.
  • 43 Morfini M, Longo G, Berntorp E. et al. Pharmacokinetics, thrombogenicity and safety of a double-treated prothrombin complex concentrate. Thromb Res 1993; 71: 175-184.
  • 44 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.
  • 45 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.
  • 46 Goudemand J, Peynet J, Chambost H. et al. A cross-over pharmacokinetic study of a double viral inactivated factor IX concentrate (15 nm filtration and SD) compared to a SD factor IX concentrate. Thromb Haemost 1998; 80: 919-924.
  • 47 White GC, Rosendaal F, Aledort LM. et al. Scientific and Standardisation Committee Communication Definitions in Haemophilia Recommendation of the Scientific Subcommittee on Factor VIII and Factor IX of the Scientific and Stan-dardisation Committee of the International Society on Thrombosis and Haem. Thromb Haemost 2001; 85: 560.
  • 48 Björkman S. Comparative pharmacokinetics of factor VIII and recombinant factor IX: for which coagulation factors should half-life change with age?. Haemophilia 2013; 19: 882-886.
  • 49 Björkman S. Population pharmacokinetics of recombinant factor IX: implications for dose tailoring. Haemophilia 2013; 19: 753-757.
  • 50 Miller GJ, Howarth DJ, Attfield JC. et al. Haemostatic factors in human peripheral afferent lymph. Thromb Haemost 2000; 83: 427-432.
  • 51 Björkman S, Berntorp E. Pharmacokinetics of coagulation factors: clinical relevance for patients with haemophilia. Clin Pharmacokinet 2001; 40: 815-832.
  • 52 Gui T, Lin H-F, Jin D-Y. et al. Circulating and binding characteristics of wild-type factor IX and certain Gla domain mutants in vivo. Blood 2002; 100: 153-158.
  • 53 Herzog E, Harris S, Henson C. et al. Biodistribution of the recombinant fusion protein linking coagulation factor IX with albumin (rIX-FP) in rats. Thromb Res 2014; 133: 900-907.
  • 54 van Geffen M, Mathijssen NCJ, Holme PA. et al. Pharmacodynamics of recombinant activated factor VII and plasma-derived factor VII in a cohort of severe FVII deficient patients. Thromb Res 2013; 132: 116-122.
  • 55 Morfini M, Batorova A, Mariani G. et al. Pharmacokinetic properties of recombinant FVIIa in inherited FVII deficiency account for a large volume of distribution at steady state and a prolonged pharmacodynamic effect. Thromb Haemost 2014; 112: 424-425.
  • 56 Stern DM, Knitter G, Kisiel W. et al. In vivo evidence of intravascular binding sites for coagulation factor IX. Br J Haematol 1987; 66: 227-232.
  • 57 Feng D, Stafford KA, Broze GJ. et al. Evidence of clinically significant extravascular stores of factor IX. J Thromb Haemost 2013; 11: 2176-2178.
  • 58 Powell JS, Pasi KJ, Ragni M V. et al. Phase 3 study of recombinant factor IX Fc fusion protein in haemophilia B. N Engl J Med 2013; 369: 2313-2323.
  • 59 Wakefield J. The Bayesian Analysis of Population Pharmacokinetic Models. J Am Stat Assoc 1996; 91: 62-75.
  • 60 McEneny-King A, Iorio A, Foster G. et al. The use of pharmacokinetics in dose individualisation of factor VIII in the treatment of haemophilia A. Expert Opin Drug Metab Toxicol 2016; 12: 1313-1321.
  • 61 Iorio A, McEneny-King A, Foster G. et al. What is the role for population pharmacokinetics in haemophilia? Int J Pharmacokin. 2017 accepted: 1–22.
  • 62 Samara E, Granneman R. Role of Population Pharmacokinetics in Drug Development. Clin Pharmacokinet 1997; 32: 294-312.
  • 63 Bulitta BJ, Landersdorfer BC, Forrest A. et al. Relevance of Pharmacokinetic and Pharmacodynamic Modelling to Clinical Care of Critically Ill Patients. Curr Pharm Biotechnol 2011; 12: 2044-2061.
  • 64 Joerger M. Covariate pharmacokinetic model building in oncology and its potential clinical relevance. AAPS J 2012; 14: 119-132.
  • 65 McEneny-King A, Foster G, Iorio A. et al. Data Analysis Protocol for the Development and Evaluation of Population Pharmacokinetic Models for Incorporation Into the Web-Accessible Population Pharmacokinetic Service – Haemophilia (WAPPS-Hemo). JMIR Res Protoc 2016; 5: e232.
  • 66 Iorio A, Keepanasseril A, Foster G. et al. Development of a Web-Accessible Population Pharmacokinetic Service–Haemophilia (WAPPS-Hemo): Study Protocol. JMIR Res Protoc JMIR Research Protocols; 2016; 5: e239.
  • 67 Monahan PE, Liesner R, Sullivan ST. et al. Safety and efficacy of investigator-prescribed BeneFIX prophylaxis in children less than 6 years of age with severe haemophilia B. Haemophilia 2010; 16: 460-468.
  • 68 Zakarija A. Factor IX replacement in surgery and prophylaxis. Blood Coagul Fibrinolysis 2004; 15 (Suppl. 02) S5-7.
  • 69 Morfini M. Secondary prophylaxis with factor IX concentrates: continuous infusion. Blood Transfus 2008; 6 (Suppl. 02) s21-25.
  • 70 Jackson SC, Yang M, Minuk L. et al. Patterns of tertiary prophylaxis in Canadian adults with severe and moderately severe haemophilia B. Haemophilia 2014; 20: e199-204.