Stability, safety, and pharmacokinetics of ganciclovir eye drops prepared from ganciclovir for intravenous infusion

  • Naoki Okumura
  • Toshiyuki Tanaka
  • Yuya Fukui
  • Noriko KoizumiEmail author
Laboratory Investigation



Hospital-prepared topical ganciclovir eye drops made from intravenous infusions are used to treat cytomegalovirus corneal endotheliitis. This study assessed the efficacy of these eye drops.

Study design

Experimental study design.


Ganciclovir solutions (0.5% and 1.0%) prepared by diluting DENOSINE® IV Infusion in saline were stored light-shielded at 4, 25, or 37°C for 12 weeks. Every two weeks during storage, macroscopic evaluation was conducted and ganciclovir concentrations were determined by high performance liquid chromatography. Ocular surface toxicity and corneal ganciclovir concentrations were evaluated following topical instillation of ganciclovir solutions in rabbits.


Ganciclovir solutions maintained transparency for 6 weeks, with precipitation appearing after 8 weeks. Ganciclovir concentrations were maintained at ~100% for 6 weeks at 4°C and 25°C and decreased gradually to 90% after 12 weeks. At 37°C, ganciclovir concentrations decreased linearly for 12 weeks. Rabbit eyes showed no ocular surface toxicity. Following instillation of 0.5% ganciclovir solution, endothelial ganciclovir concentrations were 28.0 µg/g at one hour and 4.3 µg/g at three hours.


Ganciclovir eye drops seem to be safe and penetrate the corneal endothelium. The drug in eye drop form is chemically stable for up to 6 weeks. Eye drops’ development for approval by regulatory authorities, especially with improved long-term stability, is anticipated.


Ganciclovir eye drops Cytomegalovirus corneal endotheliitis Stability Pharmacokinetics 



The authors thank Mr. Hirofumi Imai and Mr. Tetta Kurosawa for technical support. The authors thank for their professional English editing service. This study was supported by the Program for the Strategic Research Foundation at Private Universities from MEXT (Koizumi N and Okumura N).

Conflicts of interest

N. Okumura, None; T. Tanaka, None; Y. Fukui, None; N. Koizumi, None.


  1. 1.
    Khodadoust AA, Attarzadeh A. Presumed autoimmune corneal endotheliopathy. Am J Ophthalmol. 1982;93:718–22.CrossRefGoogle Scholar
  2. 2.
    Ohashi Y, Kinoshita S, Mano T, Kiritoshi A, Ohji M. Idiopathic corneal endotheliopathy. A report of two cases. Arch Ophthalmol. 1985;103:1666–8.CrossRefGoogle Scholar
  3. 3.
    Maudgal PC, Missotten L, De Clercq E, Descamps J. Varicella-zoster virus in the human corneal endothelium: a case report. Bull Soc Belge Ophtalmol. 1980;190:71–86.Google Scholar
  4. 4.
    Sutcliffe E, Baum J. Acute idiopathic corneal endotheliitis. Trans Am Ophthalmol Soc. 1983;81:86–96.Google Scholar
  5. 5.
    Robin JB, Steigner JB, Kaufman HE. Progressive herpetic corneal endotheliitis. Am J Ophthalmol. 1985;100:336–7.CrossRefGoogle Scholar
  6. 6.
    Ohashi Y, Yamamoto S, Nishida K, Okamoto S, Kinoshita S, Hayashi K, Manabe R. Demonstration of herpes simplex virus DNA in idiopathic corneal endotheliopathy. Am J Ophthalmol. 1991;112:419–23.CrossRefGoogle Scholar
  7. 7.
    Amano S, Oshika T, Kaji Y, Numaga J, Matsubara M, Araie M. Herpes simplex virus in the trabeculum of an eye with corneal endotheliitis. Am J Ophthalmol. 1999;127:721–2.CrossRefGoogle Scholar
  8. 8.
    Mimura T, Amano S, Nagahara M, Oshika T, Tsushima K, Nakanishi N, et al. Corneal endotheliitis and idiopathic sudden sensorineural hearing loss. Am J Ophthalmol. 2002;133:699–700.CrossRefGoogle Scholar
  9. 9.
    Koizumi N, Yamasaki K, Kawasaki S, Sotozono C, Inatomi T, Mochida C, et al. Cytomegalovirus in aqueous humor from an eye with corneal endotheliitis. Am J Ophthalmol. 2006;141:564–5.CrossRefGoogle Scholar
  10. 10.
    Suzuki T, Hara Y, Uno T, Ohashi Y. DNA of cytomegalovirus detected by PCR in aqueous of patient with corneal endotheliitis after penetrating keratoplasty. Cornea. 2007;26:370–2.CrossRefGoogle Scholar
  11. 11.
    Chee SP, Bacsal K, Jap A, Se-Thoe SY, Cheng CL, Tan BH. Corneal endotheliitis associated with evidence of cytomegalovirus infection. Ophthalmology. 2007;114:798–803.CrossRefGoogle Scholar
  12. 12.
    Koizumi N, Suzuki T, Uno T, Chihara H, Shiraishi A, Hara Y, et al. Cytomegalovirus as an etiologic factor in corneal endotheliitis. Ophthalmology. 2008;115(292–7):e293.Google Scholar
  13. 13.
    Anshu A, Chee SP, Mehta JS, Tan DT. Cytomegalovirus endotheliitis in Descemet’s stripping endothelial keratoplasty. Ophthalmology. 2009;116:624–30.CrossRefGoogle Scholar
  14. 14.
    Kandori M, Inoue T, Takamatsu F, Kojima Y, Hori Y, Maeda N, et al. Prevalence and features of keratitis with quantitative polymerase chain reaction positive for cytomegalovirus. Ophthalmology. 2010;117:216–22.CrossRefGoogle Scholar
  15. 15.
    Chee SP, Jap A. Immune ring formation associated with cytomegalovirus endotheliitis. Am J Ophthalmol. 2011;152(449–53):e441.Google Scholar
  16. 16.
    Kobayashi A, Yokogawa H, Higashide T, Nitta K, Sugiyama K. Clinical significance of owl eye morphologic features by in vivo laser confocal microscopy in patients with cytomegalovirus corneal endotheliitis. Am J Ophthalmol. 2012;153:445–53.CrossRefGoogle Scholar
  17. 17.
    Chu HY, Sun CC, Chuang WY, Liou SW, Ma DH, Lai CC, et al. Cytomegalovirus associated corneal endotheliitis after penetrating keratoplasty in a patient with Fuchs corneal endothelial dystrophy. Br J Ophthalmol. 2012;96:300–1.CrossRefGoogle Scholar
  18. 18.
    Chee SP, Jap A. Treatment outcome and risk factors for visual loss in Cytomegalovirus endotheliitis. Graefes Arch Clin Exp Ophthalmol. 2012;250:383–9.CrossRefGoogle Scholar
  19. 19.
    Koizumi N, Inatomi T, Suzuki T, Shiraishi A, Ohashi Y, Kandori M, et al. Clinical features and management of cytomegalovirus corneal endotheliitis: analysis of 106 cases from the Japan corneal endotheliitis study. Br J Ophthalmol. 2015;99:54–8.CrossRefGoogle Scholar
  20. 20.
    Koizumi N, Miyazaki D, Inoue T, Ohtani F, Kandori-Inoue M, Inatomi T, et al. The effect of topical application of 0.15% ganciclovir gel on cytomegalovirus corneal endotheliitis. Br J Ophthalmol. 2017;101:114–9.CrossRefGoogle Scholar
  21. 21.
    Waduthantri S, Zhou L, Chee SP. Intra-cameral level of ganciclovir gel, 0.15% following topical application for cytomegalovirus anterior segment infection: a pilot study. PLoS One. 2018;13:e0191850.CrossRefGoogle Scholar
  22. 22.
    Herriot R, Gray ES. Images in clinical medicine. Owl’s-eye cells. N Engl J Med. 1994;331:649.CrossRefGoogle Scholar
  23. 23.
    Hosogai M, Shima N, Nakatani Y, Inoue T, Iso T, Yokoo H, et al. Analysis of human cytomegalovirus replication in primary cultured human corneal endothelial cells. Br J Ophthalmol. 2015;99:1583–90.CrossRefGoogle Scholar
  24. 24.
    Field AK, Davies ME, DeWitt C, Perry HC, Liou R, et al. 9-([2-Hydroxy-1-(hydroxymethyl)ethoxy]methyl)guanine: a selective inhibitor of herpes group virus replication. Proc Natl Acad Sci USA. 1983;80:4139–43.CrossRefGoogle Scholar
  25. 25.
    Schein OD, Hibberd PL, Starck T, Baker AS, Kenyon KR. Microbial contamination of in-use ocular medications. Arch Ophthalmol. 1992;110:82–5.CrossRefGoogle Scholar
  26. 26.
    Geyer O, Bottone EJ, Podos SM, Schumer RA, Asbell PA. Microbial contamination of medications used to treat glaucoma. Br J Ophthalmol. 1995;79:376–9.CrossRefGoogle Scholar
  27. 27.
    Mason BL, Alfonso EC, Miller D. In-use study of potential bacterial contamination of ophthalmic moxifloxacin. J Cataract Refract Surg. 2005;31:1773–6.CrossRefGoogle Scholar
  28. 28.
    Leite SC, de Castro RS, Alves M, Cunha DA, Correa ME, da Silveira LA, et al. Risk factors and characteristics of ocular complications, and efficacy of autologous serum tears after haematopoietic progenitor cell transplantation. Bone Marrow Transplant. 2006;38:223–7.CrossRefGoogle Scholar
  29. 29.
    Rahman MQ, Tejwani D, Wilson JA, Butcher I, Ramaesh K. Microbial contamination of preservative free eye drops in multiple application containers. Br J Ophthalmol. 2006;90:139–41.CrossRefGoogle Scholar
  30. 30.
    Jokl DH, Wormser GP, Nichols NS, Montecalvo MA, Karmen CL. Bacterial contamination of ophthalmic solutions used in an extended care facility. Br J Ophthalmol. 2007;91:1308–10.CrossRefGoogle Scholar
  31. 31.
    Montes JA, Johnson D, Jorgensen J, McElmeel ML, Fulcher LC, Kiel JW. Potency and sterility of fortified tobramycin, fortified vancomycin, and moxifloxacin at 4, 24, and 35 degrees C for 14 days. Cornea. 2016;35:122–6.CrossRefGoogle Scholar

Copyright information

© Japanese Ophthalmological Society 2019

Authors and Affiliations

  • Naoki Okumura
    • 1
  • Toshiyuki Tanaka
    • 1
  • Yuya Fukui
    • 1
  • Noriko Koizumi
    • 1
    Email author
  1. 1.Department of Biomedical Engineering, Faculty of Life and Medical SciencesDoshisha UniversityKyotanabeJapan

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