Download PDF
Thromb Haemost 2001; 85(03): 445-449
DOI: 10.1055/s-0037-1615602
Review Article
Schattauer GmbH

Intratracheal Administration of Recombinant Human Factor IX (BeneFix™) Achieves Therapeutic Levels in Hemophilia B Dogs

K. E. Russell
1   Departments of Pathology and Laboratory Medicine
,
M. S. Read
1   Departments of Pathology and Laboratory Medicine
,
D. A. Bellinger
1   Departments of Pathology and Laboratory Medicine
,
K. Leitermann
3   Genetics Institute, Inc., Andover, Massachusetts, USA
,
B. J. Rup
3   Genetics Institute, Inc., Andover, Massachusetts, USA
,
K. P. McCarthy
3   Genetics Institute, Inc., Andover, Massachusetts, USA
,
J. C. Keith Jr.
3   Genetics Institute, Inc., Andover, Massachusetts, USA
,
S. P. Khor
3   Genetics Institute, Inc., Andover, Massachusetts, USA
,
R. G. Schaub
3   Genetics Institute, Inc., Andover, Massachusetts, USA
,
T. C. Nichols
1   Departments of Pathology and Laboratory Medicine
2   Medicine University of North Carolina, Chapel Hill, North Carolina
› Author Affiliations
Further Information

Publication History

Received 04 July 2000

Accepted after revision 12 September 2000

Publication Date:
08 December 2017 (online)

    Permissions and Reprints

Summary

The purpose of this paper was to establish proof of concept for administration of human recombinant F.IX (rF.IX) by inhalation for therapy of hemophilia B. The pharmacokinetics of intratracheal (IT) administration of rF.IX was studied in nine hemophilia B dogs randomized into 3 groups that received 200 IU/kg IT, 1000 IU/kg IT, or 200 IU/kg intravenously (IV). IT rF.IX produced therapeutic levels of F.IX antigen and activity and the pharmacokinetic parameters were consistent with a slow release from a depot site within the lungs. Bio-availability compared to IV administration was 11% for 200 IU/kg IT and 4.9% for 1000 IU/kg. The whole blood clotting time began to shorten at 2 h but F.IX bioactivity was not detected until 8 h post infusion in both IT groups. In all groups, F.IX activity was detected through 72 h post administration. These data demonstrate that biologically active rF.IX can reach the systemic circulation when given IT. Aerosolization of rF.IX may provide a needle-free therapeutic option for delivery of rF.IX to hemophilia B patients.

Key words

Factor IX - hemophilia B - inhalation therapy
 

  • References

  • 1 Liles D, Landen CN, Monroe DM, Lindley CM, Read MS, Roberts HR, Brinkhous KM. Extravascular administration of factor IX: Potential for replacement therapy of canine and human hemophilia B. Thromb Haemost 1997; 77: 944-8.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 2 Patton JS, Platz RM. Pulmonary delivery of peptides and proteins for systemic action. Adv Drug Del Rev 1992; 8: 179-96.
    CrossrefPubMedGoogle Scholar
  • 3 Hubbard RC, Casolaro MA, Mitchell M, Sellers SE, Arabia F, Matthay MA, Crystal RG. Fate of aerosolized recombinant DNA-produced alpha1-antitrypsin: Use of epithelial surface of the lower respiratory tract to administer proteins of therapeutic importance. Proc Natl Acad Sci 1989; 86: 680-4.
    CrossrefPubMedGoogle Scholar
  • 4 Brinkhous KM, Sigman JL, Read MS, Stewart PF, McCarthy KP, Timony GA, Leppanen SD, Rup BJ, Keith Jr JC, Schaub RG. Recombinant human factor IX: Replacement therapy prophylaxis pharmacokinetics, and immunogenicity in canine hemophilia B. Blood 1996; 88: 2603-10.
    PubMedGoogle Scholar
  • 5 Russel KE, Nichols TC, Elwell DR, Bellinger DA, Raymer RA, McElveen PR, Rup BJ, Keith JC, Leitermann K, McCarthy KP, Schaub RG, Read MS. Intratracheal administration of recombinant human factor IX (Benefix™) achieves therapeutic levels. Blood 1998; 92: 356a.
    PubMedGoogle Scholar
  • 6 Evans JP, Brinkhous KM, Brayer GD, Reisner HM, High KA. Canine Hemophilia, B resulting from a point mutation with unusual consequences. Proc Natl Acad Sci USA 1989; 86: 10095-9.
    CrossrefPubMedGoogle Scholar
  • 7 Kay MA, Rothenberg S, Landen CN, Bellinger DA, Leland F, Toman C, Finegold M, Thompson AR, Read MS, Brinkhous KM, Woo SLC. In vivo gene therapy of hemophilia B: Sustained partial correction in factor IX-deficient dogs. Science 1993; 262: 117-9.
    CrossrefPubMedGoogle Scholar
  • 8 Herzog R, Arruda VR, Fischer TH, Read MS, Nichols TC, High KA. Absence of circulating factor IX antigen in hemophilia B dogs of the UNC-Chapel Hill Colony. Thromb Haemost 2000; 84: 352-4.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 9 Harrison S, Clancy B, Brodeur S, Oaks P, Miller D, Drapeau D, Hamilton M, Charlebois T, Leonard M, McCarthy M, Zollner R, Adamson SR. Development of a serum-free process for recombinant factor IX expression in Chinese hamster ovary cells. Thromb Haemost 1995; 73: 1222.
    PubMedGoogle Scholar
  • 10 Foster WB, Anagnostopoulos A, Bonam D, Costigan RJ, Knight A, Sterl KS, Switzer MB, Walsh RE. Development of a process for purification of recombinant human factor IX. Blood 1995; 86: 870a.
    PubMedGoogle Scholar
  • 11 Rodriques H, Giles K, Sefton L, Griffon V, Duxbury M, Letwin B. Analytical characterization of recombinant human factor IX: Pharamacokinetic studies in the rat and the dog. Thromb Haemost 1995; 73: 1206.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 12 Keith Jr JC, Ferranti TJ, Misra B, Frederick T, Rup B, McCarthy K, Faulkner R, Bush L, Schaub RG. Evaluation of recombinant human factor IX: Pharmacokinetic studies in the rat and the dog. Thromb Haemost 1994; 73: 101-5.
    PubMedGoogle Scholar
  • 13 Lee RI, White PD. A clinical study of the coagulation time of blood. Am J Med Sci 1913; 145: 495-503.
    CrossrefPubMedGoogle Scholar
  • 14 Brinkhous KM, Landen CN, Read MS. Evaluation of sensitivity of whole blood clotting time (WBCT), partial thromboplastin time (PTT), and F. IX one-stage bioassay tests with low plasma F. IX levels observed with transfusion or gene therapy in canine hemophilia B. Blood 1993; 82 (Suppl. 01) 592a.
    PubMedGoogle Scholar
  • 15 Mustafa RL, Elwell DR, Russell KE, Nichols TC, Read MS. A role for whole blood clotting time as a sensitive screening test for F. VIII and F. IX replacement. Blood 1998; 92: 96b.
    PubMedGoogle Scholar
  • 16 Pedersen PV. Novel Deconvolution Method for Linear Pharmacokinetic Systems with Polyexponential Impulse Response. J Pharm Sci 1980; 69: 312-8.
    CrossrefPubMedGoogle Scholar
  • 17 Gerrard AJ, Austen DEG, Brownlee GG. Subcutaneous injection of factor IX for the treatment of haemophilia B. British Journal of Haematology 1992; 81: 610-3.
    CrossrefPubMedGoogle Scholar
  • 18 McCarthy KP, Timony GA, Ferranti TJ, Misra BR, Keith Jr JC, Bree AG, Schleman FJ, Resmini C, Haire TC, Schaub RG, Garzone PD. Subcutaneous bioavailability of recombinant factor IX (BeneFix™) in healthy beagle dogs and cynomolugus monkeys. Blood 1996; 88: 68b.
    PubMedGoogle Scholar
  • 19 Cheung WF, van den Born J, Kuhn K, Kjellen L, Hudson BG, Stafford DW. Identification of the endothelial cell binding site for factor IX. Proc Natl Acad Sci USA 1996; 93: 11068-73.
    CrossrefPubMedGoogle Scholar
  • 20 Wolberg AS, Stafford DW, Erie DA. Human factor IX binds to specific sites on the collagenous domain of collagen IV. J Biol Chem 1997; 272: 16717-20.
    CrossrefPubMedGoogle Scholar
  • 21 Brinkhous KM, Sigman JL, Read MS, Stewart PF, Bush L, Bartlett E, Rup B, Keith Jr JC, Garzone P, McCarthy K, Schaub RG. Subcutaneous recombinant factor IX (BeneFIX™) administration produces therapeutic levels of FIX activity in hemophilia B dogs. Blood 1996; 88: 422a.
    PubMedGoogle Scholar
  • 22 Yu J, Chien YW. Pulmonary drug delivery: Physiologic and mechanistic aspects. Crit Rev Therap Drug Carr Sys 1997; 14: 395-453.
    PubMedGoogle Scholar
  • 23 Brain JD, Knudson DE, Sorokin SP, Davis MA. Pulmonary distribution of particles given by intratracheal instillation or by aerosol inhalation. Environ Res 1976; 11: 13-33.
    CrossrefPubMedGoogle Scholar
  • 24 Colthorpe P, Farr SJ, Taylor G, Smith IJ, Wyatt D. The pharmacokinetics of pulmonary-delivered insulin: A comparison of intratracheal and aerosol administration to the rabbit. Pharm Res 1992; 9: 764-8.
    CrossrefPubMedGoogle Scholar
  • 25 Gillespie MN, Krechniak JW, Crooks PA, Altiere RJ, Olson JW. Pulmonary metabolism of exogenous enkephalins in isolated perfused rat lungs. J Pharmacol Exp Ther 1985; 232: 675-8.
    PubMedGoogle Scholar
  • 26 Jendle J, Karlberg BE, Persliden J, Franzen L, Arborelius M. Delivery and retention of an insulin aerosol produced by a new jet nebulizer. J Aersol Med 1995; 8: 243-54.
    PubMedGoogle Scholar
  • 27 Jendle JH, Karlberg BE, Arborelius M. An exploration of intrapulmonary insulin administration in anaesthetized and mechanically ventilated pigs. Scand J Clin Lab Invest 1996; 56: 251-8.
    PubMedGoogle Scholar
  • 28 Laube BL, Georgopoulos A, Adams GK. Preliminary study of the efficacy of insulin aerosol delivered by oral inhalation in diabetic patients. JAMA 1993; 269: 2106-9.
    CrossrefPubMedGoogle Scholar
  • 29 Gupta S, Moussy F, Dalby RN, Miekka SI, Bruley DF. Pulmonary delivery of human protein C and factor IX. in (ed) NaL (ed) Oxygen Transport to Tissue XVIII. New York: Plenum Press; 1997. p 429-35.
    Google Scholar
  • 30 Wigley FM, Londono JH, Wood SH, Shipp JC, Waldman RH. Insulin across respiratory mucosae by aerosol delivery. Diabetes 1971; 20: 552-6.
    CrossrefPubMedGoogle Scholar