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Pharmaceutical Research

, Volume 17, Issue 12, pp 1503–1510 | Cite as

Pharmacokinetics and Safety of an Anti-Vascular Endothelial Growth Factor Aptamer (NX1838) Following Injection into the Vitreous Humor of Rhesus Monkeys

  • Daniel W. Drolet
  • Joyce Nelson
  • Christopher E. Tucker
  • Philip M. Zack
  • Kerry Nixon
  • Richard Bolin
  • Mark B. Judkins
  • James A. Farmer
  • Julie L. Wolf
  • Stanley C. Gill
  • Raymond A. Bendele
Article

Abstract

Purpose. The objective of this study was to determine the pharmacokinetics and safety for NX1838 following injection into the vitreous humor of rhesus monkeys.

Methods. Plasma and vitreous humor pharmacokinetics were determined following a single bilateral 0.25, 0.50, 1.0, 1.5, or 2.0 mg/eye dose. In addition, the pharmacokinetics and toxicological properties of NX1838 were determined following six biweekly bilateral injections of 0.25 or 0.50 mg/eye or following four biweekly bilateral injections of 0.10 mg per eye followed by two biweekly bilateral injections of 1.0 mg per eye.

Results. Plasma and vitreous humor NX1838 concentrations were linearly related to the dose administered. NX1838 was cleared intact from the vitreous humor into the plasma with a half-life of approximately 94 h, which was in agreement with the plasma terminal half-life. Vascular endothelial growth factor (VEGF)-binding assays demonstrated that the NX1838 remaining in the vitreous humor after 28 days was fully active. No toxicological effects or antibody responses were evident.

Conclusions. The no observable effect level was greater than six biweekly bilateral 0.50 mg/eye doses or two biweekly bilateral 1.0 mg/eye doses. These pharmacokinetic and safety data support monthly 1 or 2 mg/eye dose regimens in human clinical trials.

VEGF VPF SELEX 

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REFERENCES

  1. 1.
    J. Ruckman, L. S. Green, J. Beeson, S. Waugh, W. L. Gillette, D. D. Henninger, L. Claesson-Welsh, and N. Janjic. 2'-Fluoropyrimidine RNA-based aptamers to the 165-amino acid form of vascular endothelial growth factor (VEGF165). J. Biol. Chem. 273: 20556–20567 (1998).Google Scholar
  2. 2.
    L. Gold, B. Polisky, O. Uhlenbeck, and M. Yarus. Diversity of oligonucleotide functions. Annu. Rev. Biochem. 64:763–797 (1995).Google Scholar
  3. 3.
    M. Famulok and A. Jenne. Oligonucleotide libraries—variatio delectat. Curr. Opin. Chem. Biol. 2:320–327 (1998).Google Scholar
  4. 4.
    L. S. Green, D. Jellinek, C. Bell, L. A. Beebe, B. D. Feistner, S. C. Gill, F. Jucker, and N. Janjic. Nuclease-resistant nucleic acid ligands to vascular permeability factor/vascular endothelial growth factor. Chem. Biol. 2:683–695 (1995).Google Scholar
  5. 5.
    W. A. Pieken, D. B. Olsen, F. Benseler, H. Aurup, and F. Eckstein. Kinetic characterization of ribonuclease-resistant 2'-modified hammerhead ribozymes. Science 253:314–317 (1991).Google Scholar
  6. 6.
    L. L. Cummins, S. R. Owens, L. M. Risen, E. A. Lesnik, S. M. Freler, D. McGee, C. J. Guinosso, and P. D. Cook. Characterization of fully 2'-modified oligoribonucleotide hetero-and homoduplex hybridization and nuclease sensitivity. Nucl. Acids Res. 23:2019–2024 (1995).Google Scholar
  7. 7.
    D. Jellinek, L. S. Green, C. Bell, C. K. Lynott, N. Gill, C. Vargeese, G. Kirschenheuter, D. P. C. McGee, P. Abesinghe, W. A. Pieken, R. Shapiro, D. B. Rifkin, D. Moscatelli, and N. Janjic. Potent 2'-amino-2'-deoxypyrimidine RNA inhibitors of basic fibroblast growth factor. Biochemistry 34:11363–11372 (1995).Google Scholar
  8. 8.
    M. C. Willis, B. Collins, T. Zhang, L. S. Green, D. P. Sebesta, C. Bell, E. Kellogg, S. C. Gill, A. Magallanez, S. Knauer, R. A. Bendele, P. S. Gill, and N. Janjic. Liposome-anchored vascular endothelial growth factor aptamers. Bioconj. Chem. 9:573–582 (1998).Google Scholar
  9. 9.
    J. Van Berkel, P. Chris De Smidt, T. Le Doan, and S. De Falco. Association of antisense oligonucleotides with lipoproteins prolongs the plasma half-life and modifies the tissue distribution. Nucl. Acids Res. 19:4695–4700 (1991).Google Scholar
  10. 10.
    C. Bell, E. Lynam, D. J. Landfair, N. Janjic, and M. E. Wiles. Oligonucleotide NX1838 inhibits VEGF165-mediated cellular responses in vitro. In Vitro Cell. Dev. Biol. 35:533–542 (1999).Google Scholar
  11. 11.
    B. Tomkinson, E. Brown, J. LeRay, N. Janjic, C. Vargeese, M. Willis, M. Wiles, J. Bill, L.-S. Chen, L. Wiegand, S. Gill, and D. Emerson. In vivo antitumor efficacy of a VEGF-specific antagonist aptamer in a human rhabdomyosarcoma nude mouse xenograft model. Angiogenesis and Cancer: American Association of Cancer Research special conference in cancer research, Orlando, FL. 1998.Google Scholar
  12. 12.
    R. Klein, B. E. K. Klein, S. C. Jensen, and S. M. Meuer. The five year incidence and progression of age-related maculopathy. Ophthalmology 104:7–21 (1997).Google Scholar
  13. 13.
    G. ilvestri. Age-related macular degeneration: genetics and implications for detection and treatment. Mol. Med. Today 3:84–91 (1997).Google Scholar
  14. 14.
    R. J. D'Amato and A. P. Adamis. Angiogenesis inhibition in age-related macular degeneration. Ophthalmology 102:1261–1262 (1995).Google Scholar
  15. 15.
    A. Kvanta, P. V. Algvere, L. Berglin, and S. Seregard. Subfoveal fibrovascular membranes in age-related macular degeneration express vascular endothelial growth factor. Invest. Ophthalmol. Vis. Sci. 37:1929–1934 (1996).Google Scholar
  16. 16.
    P. F. Lopez, B. D. Sippy, H. M. Lambert, A. B. Thach, and D. R. Hinton. Transdifferentiated retinal pigment epithelial cells are immunoreactive for vascular endothelial growth factor in surgically excised age-related macular degeneration-related choroidal neovascular membranes. Invest. Ophthalmol. Vis. Sci. 37:855–868 (1996).Google Scholar
  17. 17.
    M. Kliffen, H. S. Sharma, C. M. Mooy, S. Kerkvliet, and P. T. V. M. de Jong. Increased expression of angiogenic growth factors in age-related maculopathy. Br. J. Ophthalmol. 81:154–162 (1997).Google Scholar
  18. 18.
    J. A. Wells, R. Murthy, R. Chibber, A. Nunn, P. A. Molinatti, E. M. Kohner, and Z. J. Gregor. Levels of vascular endothelial growth factor are elevated in the vitreous of patients with subretinal neovascularisation. Br. J. Ophthalmol. 80:363–366 (1996).Google Scholar
  19. 19.
    J. Mordenti, A. Cuthbertson, N. Ferrara, K. Thomsen, L. Berleau, V. Licko, P. C. Allen, C. R. Valverde, Y. G. Meng, D. T.W. Fei, K. M. Fourre, and A. M. Ryan. Comparisons of the intraocular tissue distribution, pharmacokinetics, and safety of 125I-labeled full-length and Fab antibodies in rhesus monkeys following intravitreal administration. Toxicol. Pathol. 27:536–544 (1999).Google Scholar
  20. 20.
    C. E. Tucker, L.-S. Chen, M. B. Judkins, J. A. Farmer, S. C. Gill, and D. W. Drolet. Detection and plasma pharmacokinetics of an anti-vascular endothelial growth factor oligonucleotide-aptamer (NX1838) in rhesus monkeys. J. Chromatogr. Biomed. Appl. 732: 203–212 (1999).Google Scholar
  21. 21.
    P. Bridonneau, S. Bunch, R. Tengler, K. Hill, J. Carter, W. Pieken, D. Tinnermeier, R. Lehrman, and D. W. Drolet. Purification of a highly modified RNA-aptamer, effect of complete denaturation during chromatography on product recovery and specific activity. J. Chromatogr. Biomed. Appl. 726:237–247 (1999).Google Scholar
  22. 22.
    J. M. Leeds, S. P. Henry, S. Bistner, S. Scherrill, K. Williams, and A. A. Levin. Pharmacokinetics of an antisense oligonucleotide injected intravitreally in monkeys. Drug Metab. Dispos. 26:670–675 (1998).Google Scholar
  23. 23.
    J. M. Leeds, S. Henry, L. Truong, A. Zutsi, A. A. Levin, and D. Kornburst. Pharmacokinetics of a potential human cytomegalovirus therapeutic, a phosphorothioate oligonucleotide, after intravitreal injection in the rabbit. Drug Metab. Dispos. 25:921–926 (1997).Google Scholar
  24. 24.
    F. Malecaze, S. Clamens, V. Simmore-Pintel, A. Mathis, P. Chollet, C. Favard, F. Bayard, and J. Plouet. Detection of vascular endothelial growth factor messenger RNA and vascular endothelial growth factor-like activity in proliferative diabetic retinopathy. Arch. Ophthalmol. 112:1476–1482 (1994).Google Scholar

Copyright information

© Plenum Publishing Corporation 2000

Authors and Affiliations

  • Daniel W. Drolet
    • 1
  • Joyce Nelson
    • 2
  • Christopher E. Tucker
    • 3
  • Philip M. Zack
    • 3
  • Kerry Nixon
    • 2
  • Richard Bolin
    • 3
  • Mark B. Judkins
    • 2
  • James A. Farmer
    • 2
  • Julie L. Wolf
    • 3
  • Stanley C. Gill
    • 3
  • Raymond A. Bendele
    • 3
  1. 1.Gilead Sciences Inc.Boulder
  2. 2.Sierra BiomedicalSparks
  3. 3.Gilead Sciences Inc.Boulder

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