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Clinical Pharmacokinetics

, Volume 41, Issue 4, pp 255–260 | Cite as

Fomivirsen

Clinical Pharmacology and Potential Drug Interactions
  • Richard S. Geary
  • Scott P. Henry
  • Lisa R. Grillone
Review Article Drug Disposition

Abstract

Fomivirsen sodium is a 21-base phosphorothioate oligodeoxynucleotide complementary to the messenger RNA of the major immediate-early region proteins of human cytomegalovirus, and is a potent and selective antiviral agent for cytomegalovirus retinitis. Following intravitreal administration, fomivirsen is slowly cleared from vitreous with a half-life of approximately 55 hours in humans. Preclinical studies show that fomivirsen distributes to retina and is slowly metabolised by exonuclease digestion. Clearance from retina was shown to be similarly slow following loading from the vitreous. The estimated half-life for clearance of fomivirsen from retina was 78 hours in monkeys following a 115μg dose. Because of the low doses coupled with slow disposition from the eye, measurable concentrations of drug are not detected in the systemic circulation following intravitreal administration.

Systemically administered phosphorothioate oligodeoxynucleotides are highly bound to albumin and α2-macroglobulin in blood plasma. Because fomivirsen does not compete for oxidative metabolic processes involved in clearance of many xenobiotics, the most likely mechanism for drug interactions may be altered protein binding of a coadministered drug. The extremely low systemic exposure to this oligodeoxynucleotide following intravitreal administration largely negates its potential ability to interact with systemically administered drugs. Even if fomivirsen were able to access the blood, protein binding assays indicate that drugs that are site I and site II binders of albumin (warfarin, ibuprofen, salicylic acid) are not displaced in the presence of phosphorothioate oligodeoxynucleotides of various sequences at concentrations orders of magnitude higher than that seen for fomivirsen.

Administration of fomivirsen with numerous systemically administered antiretrovirals (for example zidovudine and zalcitabine) as well as systemically administered anticytomegalovirus agents such as foscarnet and ganciclovir has been reported to be well tolerated. The only reported warning is a recommendation against administration within 2 to 4 weeks of cidofovir treatment due to an increased risk of ocular inflammation.

Keywords

Ganciclovir Foscarnet Phosphorothioate Zalcitabine Normal Human Dermal Fibroblast 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgements

The authors would like to thank Camille Jordan for administrative assistance in the preparation of this manuscript.

References

  1. 1.
    Crooke ST. Basic principles of antisense therapeutics. In: Crooke ST, editor. Antisense research and applications. Berlin: Springer-Verlag, 1998: 1–50CrossRefGoogle Scholar
  2. 2.
    Crooke ST. Advances in understanding the pharmacological properties of antisense oligonucleotides. In: Benjamin BW, editor. Advances in Pharmacology. Boca Raton (FL): CRC Press, 1997: 1–49Google Scholar
  3. 3.
    Agrawal S, Temsamani J, Galbraith W, et al. Pharmacokinetics of antisense oligonucleotides. Clin Pharmacokinet 1995; 28: 7–16PubMedCrossRefGoogle Scholar
  4. 4.
    Cossum PA, Sasmor H, Dellinger D, et al. Disposition of the 14C-labeled phosphorothioate oligonucleotide ISIS 2105 after intravenous administration to rats. J Pharmacol Exp Ther 1993; 267: 1181–90PubMedGoogle Scholar
  5. 5.
    Geary RS, Leeds JM, Henry SP, et al. Antisense oligonucleotide inhibitors for the treatment of cancer: 1. Pharmacokinetic properties of phosphorothioate oligodeoxynucleotides. Anticancer Drug Des 1997; 12: 383–94PubMedGoogle Scholar
  6. 6.
    Sands H, Gorey-Feret LJ, Cocuzza AJ, et al. Biodistribution and metabolism of internally 3H-labeled oligonucleotides. I. Comparison of a phosphodiester and a phosphorothioate. Mol Pharmacol 1994; 45: 932–43PubMedGoogle Scholar
  7. 7.
    Oberbauer R, Schreiner GF, Biber J, et al. In vivo suppression of the renal Na+/Pi cotransporter by antisense oligonucleotides. Proc Natl Acad Sci U S A 1996; 93: 4903–6PubMedCrossRefGoogle Scholar
  8. 8.
    Agrawal S, Iyer RP. Perspectives in antisense therapeutics. Pharmacol Ther 1997; 76: 151–60PubMedCrossRefGoogle Scholar
  9. 9.
    Bennett CF, Butler M, Cook PD, et al. Antisense oligonucleotide-based therapeutics. In: Templeton NS, Lasic DD, Templeton NS, et al., editors. Gene therapy. New York: Marcel Dekker, Inc., 2000: 305–32Google Scholar
  10. 10.
    Detrick B, Nagineni CN, Grillone LR, et al. Inhibition of human cytomegalovirus replication in a human retinal epithelial cell model by antisense oligonucleotides. Invest Ophthalmol Vis Sci 2001; 42: 163–9PubMedGoogle Scholar
  11. 11.
    Anderson KP, Fox MC, Brown-Driver V, et al. Inhibition of human cytomegalovirus immediate-early gene expression by an antisense oligonucleotide complementary to immediateearly RNA. Antimicrob Agents Chemother 1996; 40: 2004–11PubMedGoogle Scholar
  12. 12.
    Azad RF, Driver VB, Tanaka K, et al. Antiviral activity of a phosphorothioate oligonucleotide complementary to RNA of the human cytomegalovirus major immediate-early region. Antimicrob Agents Chemother 1993; 37: 1945–54PubMedCrossRefGoogle Scholar
  13. 13.
    Azad RF, Brown-Driver V, Buckheit Jr RW, et al. Antiviral activity of a phosphorothioate oligonucleotide complementary to human cytomegalovirus RNA when used in combination with antiviral nucleoside analogs. Antiviral Res 1995; 28: 101–11PubMedCrossRefGoogle Scholar
  14. 14.
    Askari FK Mcdonnell WM. Antisense oligonucleotide therapy. N Engl J Med 1996; 334: 316–8PubMedCrossRefGoogle Scholar
  15. 15.
    Cinatl Jr J, Bittoova M, Margraf S, et al. Cytomegalovirus infection decreases expression of thrombospondin-1 and -2 in cultured human retinal glial cells: effects of antiviral agents. J Infect Dis 2000; 182: 643–51PubMedCrossRefGoogle Scholar
  16. 16.
    Cinatl Jr J, Kotchetkov R, Weimer E, et al. The antisense oligonucleotide ISIS 2922 prevents cytomegalovirus-induced upregulation of IL-8 and ICAM-1 in cultured human fibroblasts. J Med Virol 2000; 60: 313–23PubMedCrossRefGoogle Scholar
  17. 17.
    Leeds JM, Henry SP, Truong L, et al. Pharmacokinetics of a potential human cytomegalovirus therapeutic, a phosphorothioate oligonucleotide, after intravitreal injections in the rabbit. Drug Metab Dispos 1997; 25: 921–6PubMedGoogle Scholar
  18. 18.
    Leeds JM, Henry SP, Bistner S, et al. Pharmacokinetics of an antisense oligonucleotide injected intravitreally in monkeys. Drug Metab Dispos 1998; 26: 670–5PubMedGoogle Scholar
  19. 19.
    Bejanian M, Lieberman RM, Goldstein DA, et al. A pharmacokinetic study of intravitreal fomivirsen (Vitravene™) in patients with CMVR. ARVO Annual Meeting; 1999 May 9–14; Fort Lauderdale (FL): IOVS, 1999; 40: 5874Google Scholar
  20. 20.
    Flores-Aquilar M, Besen G, Vuong C, et al. Evaluation of retinal toxicity and efficacy of anti-cytomegalovirus and anti-herpes simplex virus antiviral phosphorothioate oligonucleotides ISIS 2922 and ISIS 4015. J Infect Dis 1997; 175: 1308–16CrossRefGoogle Scholar
  21. 21.
    Perry CM, Balfour JA. Fomivirsen. Drugs 1999; 57: 375–80PubMedCrossRefGoogle Scholar
  22. 22.
    Levin AA, Monteith DK, Leeds JM, et al. Toxicity of oligodeoxynucleotide therapeutic agents. In: Crooke ST, editor. Antisense research and applications. Berlin: Springer-Verlag, 1998: 169–215CrossRefGoogle Scholar
  23. 23.
    Brown DA, Kang S-H, Gryaznov SM, et al. Effect of phosphorothioate modification of oligodeoxynucleotides on specific protein binding. J Biol Chem 1994; 269: 26801–5PubMedGoogle Scholar
  24. 24.
    Phillips JA, Craig SJ, Bayley D, et al. Pharmacokinetics, metabolism and elimination of a 20-mer phosphorothioate oligodeoxynucleotide (CGP 69846A) after intravenous and subcutaneous administration. Biochem Pharmacol 1997; 54: 657–68PubMedCrossRefGoogle Scholar
  25. 25.
    Geary RS, Leeds JM, Fitchett J, et al. Pharmacokinetics and metabolism in mice of a phosphorothioate oligonucleotide antisense inhibitor of C-raf-1 kinase expression. Drug Metab Dispos 1997; 25: 1272–81PubMedGoogle Scholar
  26. 26.
    Yu RZ, Geary RS, Leeds JM, et al. Comparison of pharmacokinetics and tissue disposition of an antisense phosphorothioate oligonucleotide targeting human Ha-ras mRNA in mouse and monkey. J Pharm Sci 2001; 90: 182–93PubMedCrossRefGoogle Scholar
  27. 27.
    Nicklin P, Craig S, Phillips J. Pharmacokinetic properties of phosphorothioates in animals -absorption, distribution, metabolism and elimination. In: Crooke ST, editor. Antisense research and applications. Berlin: Springer-Verlag, 1998: 141–68CrossRefGoogle Scholar
  28. 28.
    Leeds JM, Geary RS. Pharmacokinetic properties of phosphorothioate oligonucleotides in humans. In: Crooke ST, editor. Antisense research and applications. Berlin: Springer-Verlag, 1998: 217–31CrossRefGoogle Scholar
  29. 29.
    Gaus HJ, Owens SR, Winniman M, et al. On-line HPLC electrospray mass spectrometry of phosphorothioate oligonucleotide metabolites. Anal Chem 1997; 69: 313–9PubMedCrossRefGoogle Scholar
  30. 30.
    Temsamani J, Roskey A, Chaix C, et al. In vivo metabolic profile of a phosphorothioate oligodeoxynucleotide. Antisense Nucleic Acid Drug Dev 1997; 7: 159–65PubMedCrossRefGoogle Scholar
  31. 31.
    Iversen PL, Coppie BL, Tewary HK, et al. Continuous infusion of antisense phosphorothioate therapeutics. In: Agrawol S, editor. Methods in molecular medicine: antisense therapeutics Totowa (NJ): Humana Press Inc., 1996: 201–12Google Scholar
  32. 32.
    Agrawal S, Zhang X, Cai Q, et al. Effect of aspirin on protein binding and tissue disposition of oligonucleotide phosphorothioate in rats. J Drug Target 1998; 5: 303–12PubMedCrossRefGoogle Scholar
  33. 33.
    Vitravene™ (fomivirsen sodium intravitreal injectable) [prescribing information]. Duluth (GA): CibaVision, 1998Google Scholar
  34. 34.
    Nichols WG, Boeckh M. Recent advances in the therapy and prevention of CMV infections. J Clin Virol 2000; 16: 25–40PubMedCrossRefGoogle Scholar

Copyright information

© Adis International Limited 2002

Authors and Affiliations

  • Richard S. Geary
    • 1
  • Scott P. Henry
    • 1
  • Lisa R. Grillone
    • 2
  1. 1.Isis PharmaceuticalsCarlsbadUSA
  2. 2.ISTA PharmaceuticalsIrvineUSA

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