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.
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Gardner TW, Antonetti DA, Barber AJ, LaNoue KF, Levison SW . Diabetic retinopathy: more than meets the eye. Surv Ophthalmol 2002; 47 Suppl 2: S253–62.
Li W, Yanoff M, Jian B, He Z . Altered mRNA levels of antioxidant enzymes in pre-apoptotic pericytes from human diabetic retinas. Cell Mol Biol (Noisy-le-grand) 1999; 45: 59–66.
Zhang J, Wu Y, Jin Y, Ji F, Sinclair SH, Luo Y, et al. Intravitreal injection of erythropoietin protects both retinal vascular and neuronal cells in early diabetes. Invest Ophthalmol Vis Sci 2008; 49: 732–42.
Sharpies EJ, Thiemermann C, Yaqoob MM . Novel applications of recombinant erythropoietin. Curr Opin Pharmacol 2006; 6: 184–9.
Ghezzi P, Brines M . Erythropoietin as an antiapoptotic, tissue-protective cytokine. Cell Death Differ 2004; 11 Suppl 1: S37–44.
Xie Z, Wu X, Qiu Q, Gong Y, Song Y, Gu Q, et al. Expression pattern of erythropoietin and erythropoietin receptor in experimental model of retinal detachment. Curr Eye Res 2007; 32: 757–64.
Tsai JC, Wu L, Worgul B, Forbes M, Cao J . Intravitreal administration of erythropoietin and preservation of retinal ganglion cells in an experimental rat model of glaucoma. Curr Eye Res 2005; 30: 1025–31.
King CE, Rodger J, Bartlett C, Esmaili T, Dunlop SA, Beazley LD . Erythropoietin is both neuroprotective and neuroregenerative following optic nerve transection. Exp Neurol 2007; 205: 48–55.
Jolling K, Perez Ruixo JJ, Hemeryck A, Vermeulen A, Greway T . Mixed-effects modelling of the interspecies pharmacokinetic scaling of pegylated human erythropoietin. Eur J Pharm Sci 2005; 24: 465–75.
Yoon WH, Park SJ, Kim IC, Lee MG . Pharmacokinetics of recombinant human erythropoietin in rabbits and 3/4 nephrectomized rats. Res Commun Mol Pathol Pharmacol 1997; 96: 227–40.
Jurado Garcia JM, Torres Sanchez E, Olmos Hidalgo D, Alba Conejo E . Erythropoietin pharmacology. Clin Transl Oncol 2007; 9: 715–22.
Hanna L . Epoietin alfa (EPO) for anemia. BETA 1998: 40: 42.
Goy A, Belanger C, Casadevall N, Picard F, Guesnu M, Jaulmes D, et al. High doses of intravenous recombinant erythropoietin for the treatment of anaemia in myelodysplastic syndrome. Br J Haematol 1993; 84: 232–7.
Eschbach JW, Abdulhadi MH, Browne JK, Delano BG, Downing MR, Egrie JC, 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.
Kanbay M, Akcay A, Delibasi T, Uz B, Kaya A, Koca C, et al. Comparison of effects of darbepoetin alfa and epoetin alfa on serum endothelin level and blood pressure. Adv Ther 2007; 24: 346–52.
Luft FC . Erythropoietin and arterial hypertension. Clin Nephrol 2000; 53 (1 Suppl): S61–4.
Ribatti D, Vacca A, Roccaro AM, Crivellato E, Presta M . Erythropoietin as an angiogenic factor. Eur J Clin Invest 2003; 33: 891–6.
Becerra SP, Amaral J . Erythropoietin-an endogenous retinal survival factor. N Engl J Med 2002; 347: 1968–70.
Song BJ, Cai H, Gomes N, Chang S, Tsai J, Forbes M, 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.
Bakri SJ, Snyder MR, Reid JM, Pulido JS, Singh RJ . Pharmacokinetics of intravitreal bevacizumab (Avastin). Ophthalmology 2007; 114: 855–9.
Fauser S, Kalbacher H, Alteheld N, Koizumi K, Krohne TU, Joussen AM . Pharmacokinetics and safety of intravitreally delivered etanercept. Graefes Arch Clin Exp Ophthalmol 2004; 242: 582–6.
Boelaert JR, Schurgers ML, Matthys EG, Belpaire FM, Daneels RF, De Cre MJ, 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.
Sytkowski AJ, Lunn ED, Davis KL, Feldman L, Siekman S . Human erythropoietin dimers with markedly enhanced in vivo activity. Proc Natl Acad Sci USA 1998; 95: 1184–8.
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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).
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Zhang, Jf., Wu, Yl., Xu, Jy. et al. Pharmacokinetic and toxicity study of intravitreal erythropoietin in rabbits. Acta Pharmacol Sin 29, 1383–1390 (2008). https://doi.org/10.1111/j.1745-7254.2008.00885.x
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DOI: https://doi.org/10.1111/j.1745-7254.2008.00885.x
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