Original Article | Published:

Pharmacokinetics and Pharmaceutics

Pharmacokinetic and toxicity study of intravitreal erythropoietin in rabbits

Acta Pharmacologica Sinica volume 29, pages 13831390 (2008) | Download Citation

This work was supported by the following research grants: China National Program on Key Basic Research Project (973), No 2004CB-720300; Unrestricted Research Fund from the Clear Vision Foundation, Philadelphia USA; Sciences and Technology Commission of Shanghai Municipality International Cooperative Research Grant (No 054107058 and 08410701200).

Abstract

Aim:

To study the pharmacokinetics and toxicity of intravitreal erythropoietin (EPO) for potential clinical use.

Methods:

For toxicity study, 4 groups (60 rabbits) with intravitreal injection (IVit) of EPO were studied (10U, 100U, or 1 000U) per eye for single injection and 0.6 U/eye (the designed therapeutic level in rabbits) for monthly injections (6×). Eye examination, flash electroretinogram (ERG), and fluorescein angiography (FA) were carried out before and after injection. The rabbits were killed for histological study at different intervals. For the pharmacokinetic study, after IVit of 5 U EPO into left eyes, 44 rabbits were killed at different intervals, and the EPO levels in vitreous, aqueous, retina and serum were analyzed by enzyme-linked immunosorbent assay.

Results:

At all of the time points examined, the eyes were within normal limits. No significant ERG or FA change was observed. The histology of retina remained unchanged. The pharmacokinetic profile of EPO in ocular compartments was summarized as follows. The half-life times of EPO in vitreous, aqueous and serum were 2.84, 3.24 and 2.12 d, respectively; and Cmax were 4615.75, 294.31 and 1.60 U/L, respectively. EPO concentrations in the retina of the injected eye peaked at 1.36 U/g protein at 6 h following injection, with the half-life observed to be 3.42 d.

Conclusions:

IVit of EPO in a wide range is well tolerated and safe for rabbit eyes. At doses up to 10-fold higher than therapeutic levels, EPO has a pharmacokinetic profile with faster clearance, which is favorable for episodic IVit.

References

  1. 1.

    , , , , . Diabetic retinopathy: more than meets the eye. Surv Ophthalmol 2002; 47 Suppl 2: S253–62.

  2. 2.

    , , , . Altered mRNA levels of antioxidant enzymes in pre-apoptotic pericytes from human diabetic retinas. Cell Mol Biol (Noisy-le-grand) 1999; 45: 59–66.

  3. 3.

    , , , , , et al. Intravitreal injection of erythropoietin protects both retinal vascular and neuronal cells in early diabetes. Invest Ophthalmol Vis Sci 2008; 49: 732–42.

  4. 4.

    , , . Novel applications of recombinant erythropoietin. Curr Opin Pharmacol 2006; 6: 184–9.

  5. 5.

    , . Erythropoietin as an antiapoptotic, tissue-protective cytokine. Cell Death Differ 2004; 11 Suppl 1: S37–44.

  6. 6.

    , , , , , et al. Expression pattern of erythropoietin and erythropoietin receptor in experimental model of retinal detachment. Curr Eye Res 2007; 32: 757–64.

  7. 7.

    , , , , . Intravitreal administration of erythropoietin and preservation of retinal ganglion cells in an experimental rat model of glaucoma. Curr Eye Res 2005; 30: 1025–31.

  8. 8.

    , , , , , . Erythropoietin is both neuroprotective and neuroregenerative following optic nerve transection. Exp Neurol 2007; 205: 48–55.

  9. 9.

    , , , , . Mixed-effects modelling of the interspecies pharmacokinetic scaling of pegylated human erythropoietin. Eur J Pharm Sci 2005; 24: 465–75.

  10. 10.

    , , , . Pharmacokinetics of recombinant human erythropoietin in rabbits and 3/4 nephrectomized rats. Res Commun Mol Pathol Pharmacol 1997; 96: 227–40.

  11. 11.

    , , , . Erythropoietin pharmacology. Clin Transl Oncol 2007; 9: 715–22.

  12. 12.

    . Epoietin alfa (EPO) for anemia. BETA 1998: 40: 42.

  13. 13.

    , , , , , et al. High doses of intravenous recombinant erythropoietin for the treatment of anaemia in myelodysplastic syndrome. Br J Haematol 1993; 84: 232–7.

  14. 14.

    , , , , , et al. Recombinant human erythropoietin in anemic patients with end-stage renal disease. Results of a phase III multi-center clinical trial. Ann Intern Med 1989; 111: 992–1000.

  15. 15.

    , , , , , et al. Comparison of effects of darbepoetin alfa and epoetin alfa on serum endothelin level and blood pressure. Adv Ther 2007; 24: 346–52.

  16. 16.

    . Erythropoietin and arterial hypertension. Clin Nephrol 2000; 53 (1 Suppl): S61–4.

  17. 17.

    , , , , . Erythropoietin as an angiogenic factor. Eur J Clin Invest 2003; 33: 891–6.

  18. 18.

    , . Erythropoietin-an endogenous retinal survival factor. N Engl J Med 2002; 347: 1968–70.

  19. 19.

    , , , , , et al. Ocular Safety of Serial Intravitreal Injections of Recombinant Human Erythropoietin: A 7 Month Study in Rabbits [CD-ROM]. Fort Lauderdale: The Association for Research in Vision and Ophthalmology; 2008.

  20. 20.

    , , , , . Pharmacokinetics of intravitreal bevacizumab (Avastin). Ophthalmology 2007; 114: 855–9.

  21. 21.

    , , , , , . Pharmacokinetics and safety of intravitreally delivered etanercept. Graefes Arch Clin Exp Ophthalmol 2004; 242: 582–6.

  22. 22.

    , , , , , et al. Comparative pharmacokinetics of recombinant erythropoietin administered by the intravenous, subcutaneous, and intraperitoneal routes in continuous ambulatory peritoneal dialysis (CAPD) patients. Perit Dial Int 1989; 9: 95–8.

  23. 23.

    , , , , . Human erythropoietin dimers with markedly enhanced in vivo activity. Proc Natl Acad Sci USA 1998; 95: 1184–8.

Download references

Author information

Author notes

    • Wei-ye Li
    •  & Guo-tong Xu

    Wei-ye Li and Guo-tong Xu contributed equally to this study.

Affiliations

  1. Laboratory of Clinical Visual Sciences, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai JiaoTong University School of Medicine, Shanghai 200025, China

    • Jing-fa Zhang
    • , Ya-lan Wu
    • , Jing-ying Xu
    • , Luo Lu
    • , Wei Dai
    • , Wei-ye Li
    •  & Guo-tong Xu
  2. Department of Ophthalmology, Huashan Hospital Affiliated to Fudan University, Shanghai 200040, China

    • Wen Ye
    • , Yu Zhang
    •  & Huan Weng
  3. Department of Ophthalmology, Shanghai Ninth People s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China

    • Wo-dong Shi
  4. Department of Ophthalmology, Second Affiliated Hospital of Suzhou University, Suzhou 215004, China

    • Guo-xu Xu
  5. Department of Ophthalmology, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100730, China

    • Wei-ye Li
  6. Laboraotry of Clinical Visual Sciences, Tongji Eye Institute, and Department of Regenerative Medicine, Tongji University School of Medicine, Shanghai 200092, China

    • Guo-tong Xu
  7. Department of Ophthalmology, Drexel University College of Medicine, Philadelphia, Pennsylvania, USA

    • Stephen H Sinclair
    •  & Wei-ye Li

Authors

  1. Search for Jing-fa Zhang in:

  2. Search for Ya-lan Wu in:

  3. Search for Jing-ying Xu in:

  4. Search for Wen Ye in:

  5. Search for Yu Zhang in:

  6. Search for Huan Weng in:

  7. Search for Wo-dong Shi in:

  8. Search for Guo-xu Xu in:

  9. Search for Luo Lu in:

  10. Search for Wei Dai in:

  11. Search for Stephen H Sinclair in:

  12. Search for Wei-ye Li in:

  13. Search for Guo-tong Xu in:

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1111/j.1745-7254.2008.00885.x

Further reading