Journal of Clinical Immunology

, Volume 30, Issue 2, pp 321–329 | Cite as

Efficacy, Pharmacokinetics, Safety, and Tolerability of Flebogamma® 10% DIF, a High-Purity Human Intravenous Immunoglobulin, in Primary Immunodeficiency

  • Melvin Berger
  • Paul J. Pinciaro
  • Arthur Althaus
  • Mark Ballow
  • Akhilesh Chouksey
  • James Moy
  • Hans Ochs
  • Mark Stein



Flebogamma® 10% DIF represents an evolution of intravenous immune globulin from the previous 5% product to be administered at higher rates and with smaller infusion volumes. Pathogen safety is enhanced by the combination of multiple methods with different mechanisms of action.


The objective of this study as to evaluate the efficacy, pharmacokinetics, and safety of Flebogamma® 10% DIF for immunoglobulin replacement therapy in primary immunodeficiency diseases (PIDD).


Flebogamma® 10% DIF was administered to 46 subjects with well-defined PIDD at a dose of 300–600 mg/kg every 21–28 days for 12 months.


Serious bacterial infection rate was 0.025/subject/year. Half-life in serum of the administered IgG was approximately 35 days. No serious treatment-related adverse event (AE) occurred in any patient. Most of the potentially treatment-related AEs occurred during the infusion, accounting for 20% of the 601 infusions administered.


Flebogamma® 10% DIF is efficacious and safe, has adequate pharmacokinetic properties, and is well-tolerated for the treatment of PIDD.


Intravenous immune globulin Flebogamma® 10% DIF IGIV clinical trial primary immunodeficiency disease nanofiltration 


  1. 1.
    Berger M. A history of immune globulin therapy, from the Harvard crash program to monoclonal antibodies. Curr Allergy Asthma Rep. 2002;2:368–78.CrossRefPubMedGoogle Scholar
  2. 2.
    Eibl MM. History of immunoglobulin replacement. Immunol Allergy Clin North Am. 2008;28:737–64.CrossRefPubMedGoogle Scholar
  3. 3.
    Outbreak of hepatitis C associated with intravenous immunoglobulin administration—United States, October 1993–June 1994 (1994) MMWR Morb Mortal Wkly Rep 43:505–509Google Scholar
  4. 4.
    Kempf C, Stucki M, Boschetti N. Pathogen inactivation and removal procedures used in the production of intravenous immunoglobulin. Biologicals. 2007;35:35–42.CrossRefPubMedGoogle Scholar
  5. 5.
    Horowitz B, Wiebe ME, Lippin A, Stryker MH. Inactivation of viruses in labile blood derivatives. 1. Disruption of lipid-enveloped viruses by tri-(n-butyl) phosphate detergent combinations. Transfusion. 1985;25:516–22.CrossRefPubMedGoogle Scholar
  6. 6.
    Korneyeva M, Hotta J, Lebing W, Rosenthal RS, Franks L, Petteway SR Jr. Enveloped virus inactivation by caprylate—a robust alternative to solvent detergent treatment in plasma derived intermediates. Biologicals. 2002;30:153–62.CrossRefPubMedGoogle Scholar
  7. 7.
    Louie RE, Galloway CJ, Dumas ML, et al. Inactivation of hepatitis C virus in low pH Intravenous immunoglobulin. Biologicals. 1994;22:13–9.CrossRefPubMedGoogle Scholar
  8. 8.
    Burnouf T, Radosevich M. Nanofiltration of plasma-derived biopharmaceutical products. Haemophilia. 2003;9:24–37.CrossRefPubMedGoogle Scholar
  9. 9.
    O'Grady J, Losikoff A, Poiley J, Fickett D, Oliver C. Virus removal studies using nanofiltration membranes. Dev Biol Stand. 1996;88:319–26.PubMedGoogle Scholar
  10. 10.
    Soluk L, Price H, Sinclair C, Atalla-Mikhail D, Genereux M. Pathogen safety of intravenous Rh immunoglobulin liquid and other immune globulin products: enhanced nanofiltration and manufacturing process overview. Am J Ther. 2008;15:435–43.CrossRefPubMedGoogle Scholar
  11. 11.
    Kumar A, Teuber SS, Gershwin ME. Current perspectives on primary immunodeficiency diseases. Clin Dev Immunol. 2006;13:223–59.CrossRefPubMedGoogle Scholar
  12. 12.
    Berger M. Principles of and advances in immunoglobulin replacement therapy for primary immunodeficiency. Immunol Allergy Clin North Am. 2008;28:413–37.CrossRefPubMedGoogle Scholar
  13. 13.
    Hooper J. intravenous immunoglobulins: evolution of commercial IGIV preparations. Immunol Allergy Clin North Am. 2008;28:765–78.CrossRefPubMedGoogle Scholar
  14. 14.
    Jorquera JI. Flebogamma 5% DIF development: rationale for a new option in intravenous immunoglobulin therapy. Clin Exp Immunol. 2009;157(Suppl 1):17–21.CrossRefPubMedGoogle Scholar
  15. 15.
    Vlug A, Nieuwenhuys EJ, van Eijk RV, Geertzen HG, van Houte AJ. Nephelometric measurements of human IgG subclasses and their reference ranges. Ann Biol Clin (Paris). 1994;52:561–7.Google Scholar
  16. 16.
    US FDA Compliance program guidance manual. Chapter 42—Blood and blood products inspection of source plasma establishments, brokers, testing laboratories and contractors. Accessed 27 December 2008
  17. 17.
    Code of Federal Regulations, Title 21, Volume7. CFR21 Part 640. April 1, 2008Google Scholar
  18. 18.
    Berger M, Flebogamma® 5% DIF® Investigators. A multicenter, prospective, open label, historically controlled clinical trial to evaluate efficacy and safety in primary immunodeficiency disease patients of Flebogamma 5% DIF®, the next generation of Flebogamma. J Clin Immunol. 2007;27:628–33.CrossRefPubMedGoogle Scholar
  19. 19.
    Belda FJ, Otegui M, Caballero S, Domingo N, Díez JM, Gajardo R, et al. Viral safety studies of FlebogammaDIF®. Clin Exp Immunol. 2008;154:209.CrossRefGoogle Scholar
  20. 20.
    US FDA. Guidance for industry: safety, efficacy and pharmacokinetic studies to support marketing of immune globulin intravenous (human) as replacement therapy for primary immune deficiency. Accessed 25 March 2009
  21. 21.
    Berger M, Pinciaro PJ, Flebogamma 5% Investigators. Safety, efficacy and pharmacokinetics of Flebogamma 5% for replacement therapy in primary immune deficiency. J Clin Immunol. 2004;24:389–96.CrossRefPubMedGoogle Scholar
  22. 22.
    Heatherington AC, Vinci P, Golde H. A pharmacokinetic/pharmacodynamic comparison of SAAM II and PC/WinNonlin modeling software. J Pharm Sci. 1998;87:1255–63.CrossRefPubMedGoogle Scholar
  23. 23.
    Official Disability Guidelines. Accessed 25 March 2009
  24. 24.
    Centers for Disease Control and Prevention. FastStats. Accessed 25 March 2009
  25. 25.
    Bonagura VR, Marchlewski R, Cox A, Rosenthal DW. Biologic IgG level in primary immunodeficiency disease: the IgG level that protects against recurrent infection. J Allergy Clin Immunol. 2008;122:210–2.CrossRefPubMedGoogle Scholar
  26. 26.
    Daw Z, Padmore R, Neurath D, Cober N, Tokessy M, Desjardins D, et al. Hemolytic transfusion reactions after administration of intravenous immune (gamma) globulin: a case series analysis. Transfusion. 2008;48:1598–601.CrossRefPubMedGoogle Scholar
  27. 27.
    Stein MR, Nelson RP, Church JA, Wasserman RL, Borte M, Vermylen C, et al. Safety and efficacy of PrIGIVen®, a novel 10% liquid immunoglobulin preparation for intravenous use, in patients with primary immunodeficiencies. J Clin Immunol. 2009;29:137–44.CrossRefPubMedGoogle Scholar
  28. 28.
    Pierce LR, Jain N. Risks associated with the use of intravenous immunoglobulin. Transfus Med Rev. 2003;17:241–51.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • Melvin Berger
    • 1
  • Paul J. Pinciaro
    • 2
  • Arthur Althaus
    • 3
  • Mark Ballow
    • 4
  • Akhilesh Chouksey
    • 5
  • James Moy
    • 6
  • Hans Ochs
    • 7
  • Mark Stein
    • 8
  1. 1.Case Western Reserve UniversityClevelandUSA
  2. 2.Grifols Biologicals Inc.MillersvilleUSA
  3. 3.Kentuckiana Asthma and Allergy CenterLouisvilleUSA
  4. 4.Women and Children’s Hospital of Buffalo, Division of Allergy & Immunology, Department of PediatricsSUNY BuffaloBuffaloUSA
  5. 5.Rainbow Babies and Children’s HospitalClevelandUSA
  6. 6.Rush Presbyterian St. Luke’s Medical CenterChicagoUSA
  7. 7.University of WashingtonSeattleUSA
  8. 8.Allergy Associates of the Palm BeachesNorth Palm BeachUSA

Personalised recommendations