Changes of intraocular drug concentration and pharmacokinetics of bevacizumab with annexin A5-associated liposome topically applied in the rabbit eyes_Chinese Journal of Ocular Fundus Diseases

Authors：

 Zhang Haitao , Zhang Jie , Wang Feng , Ren Yanfan , Wang Baojun

Department of Ophthalmology, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang 453100, China [Zhang Haitao (now working at Eye Hospital of Henan province & Henan Eye Institute, Henan Provincial People’s Hospital), Zhang Jie, Ren Yanfan, Wang Baojun]; Basic Medical College, Xinxiang Medical University, Xinxiang 453003, China (Wang Feng);

Corresponding author：

Zhang Haitao, Email: zhanght525@163.com

Keywords：

Angiogenesis inhibitors/therapeutic use; Annexin A5/therapeutic use; Pharmacokinetics; Animal experimentation

DOI：

10.3760/cma.j.issn.1005-1015.2017.02.015

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Objectives To explore intraocular drug concentration changes and the pharmacokinetics after topically applied of bevacizumab with annexin A5-associated liposome on rabbit eyes. Methods A total of 105 healthy New Zealand white rabbits were selected and divided randomly into 3 groups (group A, B and C), and each group had 35 rats. Bevacizumab with annexin A5-associated liposome, bevacizumab liposome and bevacizumab were topically applied 50 μl respectively on right eyes of rabbits in group A, B and C, respectively. Aqueous, vitreous body and retina/choroid were obtained at 5, 15, 30 minutes and 1, 2, 4, 8 hours and the free bevacizumab concentrations in these ocular tissues were measured by ELISA (enzyme linked immunosorbent assay). DAS 2.1.1 software was used to fit the pharmacokinetic parameters. Results The peak drug concentrations in aqueous humor of the eyes in group A, B, C were at 15 minutes after topical administration and the difference was statistically significant (F=301.061,P＜0.01). The peak drug concentrations in vitreous of the eyes in the group A, B, C were at 2 hours after topical administration and the difference was statistically significant (F=885.997,P＜0.01). The peak drug concentrations in retina/choroid of the eyes in the group A, B, C were at 1 hour after topical administration and the difference was statistically significant (F=644.908,P＜0.01). Least significant difference pair-wise test found that the drug concentrations in aqueous humor, vitreous and retina/choroid of group A was higher than that of the group B and C respectively (P＜0.05), while that of the group B and C had no significant different (P＞0.05). Pharmacokinetic fitting analysis found that the half-life (t_½) of bevacizumab in aqueous humor were 1.14, 1.29, 1.29 hours, the distribution t_½ were 1.40, 1.50, 1.42 hours and the eliminated t_½ were 2.62, 2.84, 2.73 hours in vitreous, the distribution t_½ were 2.61, 2.99, 2.70 hours and the eliminated t_½ were 2.61, 2.99, 2.70 hours in retina/choroid respectively for the 3 groups. Changes of bevacizumab concentration in aqueous humor of rabbit eyes for 3 groups was complied with one compartment model, and that in vitreous body and retina/choroid complied with two compartment model. Conclusions Topically applied annexin A5-associated liposome has higher ocular concentrations of bevacizumab than those of controls. Changes of bevacizumab concentration in aqueous humor of rabbit eyes was complied with one compartment model, and that in vitreous body and retina/choroid complied with two compartment model.

Citation： Zhang Haitao, Zhang Jie, Wang Feng, Ren Yanfan, Wang Baojun. Changes of intraocular drug concentration and pharmacokinetics of bevacizumab with annexin A5-associated liposome topically applied in the rabbit eyes. Chinese Journal of Ocular Fundus Diseases, 2017, 33(2): 176-180. doi: 10.3760/cma.j.issn.1005-1015.2017.02.015 Copy

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10.	Davis BM, Normando EM, Guo L, et al. Topical delivery of Avastin to the posterior segment of the eye in vivo using annexin A5-associated liposomes[J]. Small, 2014, 10(8): 1575-1584. DOI: 10.1002/smll.201303433.
11.	Nomoto H, Shiraga F, Kuno N, et al. Pharmacokinetics of bevacizumab after topical, subconjunctival, and intravitreal administration in rabbits[J]. Invest Ophthalmol Vis Sci, 2009, 50(10): 4807-4813. DOI: 10.1167/iovs.08-3148.
12.	Dastjerdi MH, Sadrai Z, Saban DR, et al. Corneal penetration of topical and subconjunctival bevacizumab[J]. Invest Ophthalmol Vis Sci, 2011, 52(12): 8718-8723. DOI: 10.1167/iovs.11-7871.
13.	Moisseiev E, Waisbourd M, Ben-Artsi E, et al. Pharmacokinetics of bevacizumab after topical and intravitreal administration in human eyes[J]. Graefe’s Arch Clin Exp Ophthalmol, 2014, 252(2): 331-337. DOI: 10.1007/s00417-013-2495-0.
14.	Sella R, Gal-Or O, Livny E, et al. Efficacy of topical aflibercept versus topical bevacizumab for the prevention of corneal neovascularization in a rat model[J]. Exp Eye Res, 2016, 146:224-232. DOI: 10.1016/j.exer.2016.03.021.
15.	Motarjemizadeh Q, Aidenloo NS, Sepehri S. A comparative study of different concentrations of topical bevacizumab on the recurrence rate of excised primary pterygium: a short-term follow-up study[J]. Int Ophthalmol, 2016, 36(1): 63-71. DOI: 10.1007/s10792-015-0076-4.
16.	Wang Y, Fei D, Vanderlaan M, et al. Biological activity of bevacizumab, a humanized anti-VEGF antibody in vitro[J]. Angio-genesis, 2004, 7(4): 335-345. DOI:10.1007/s10456-004-8272-2.

1. Park SJ, Choi Y, Na YM, et al. Intraocular pharmacokinetics of intravitreal aflibercept (Eylea) in a rabbit model[J]. Invest Ophthalmol Vis Sci, 2016, 57(6): 2612-2617. DOI: 10.1167/iovs.16-19204.
2. Li H, Lei N, Zhang M, et al. Pharmacokinetics of a long-lasting anti-VEGF fusion protein in rabbit[J]. Exp Eye Res, 2012, 97(1): 154-159. DOI: 10.1016/j.exer.2011.09.002.
3. Xu W, Wang H, Wang F, et al. Testing toxicity of multiple intravitreal injections of bevacizumab in rabbit eyes[J]. Can J Ophthalmol, 2010, 45(4): 386-392. DOI: 10.3129/i10-024.
4. Tabandeh H, Boscia F, Sborgia A, et al. Endophthalmitis associated with intravitreal injections: office-based setting and operating room setting[J]. Retina, 2014, 34(1): 18-23. DOI: 10.1097/IAE.000000 0000000008.
5. Agrawal S, Joshi M, Christoforidis JB. Vitreous inflammation associated with intravitreal anti-VEGF pharmacotherapy[J/OL]. Mediators Inflamm, 2013, 2013:943409[2013-11-06]. . DOI: 10.1155/2013/ 943409.
6. Rayess N, Rahimy E, Storey P, et al. Postinjection endophthalmitis rates and characteristics following intravitreal bevacizumab, ranibizumab, and aflibercept[J]. Am J Ophthalmol, 2016, 165:88-93. DOI: 10.1016/j.ajo.2016.02.028.
7. Kaur IP, Kakkar S. Nanotherapy for posterior eye diseases[J]. J Control Release, 2014, 193:100-112. DOI: 10.1016/j.jconrel. 2014.05.031.
8. Ungethüm L, Kenis H, Nicolaes GA, et al. Engineered annexin A5 variants have impaired cell entry for molecular imaging of apoptosis using pretargeting strategies[J]. J Biol Chem, 2010, 286(3): 1903-1910. DOI: 10.1074/jbc.M110.163527.
9. Abrishami M, Ganavati SZ, Soroush D, et al. Preparation, characterization, and in vivo evaluation of nanoliposomes-encapsulated bevacizumab (Avastin) for intravitreal administration[J]. Retina, 2009, 29(5): 699-703. DOI: 10.1097/ IAE.0b013e3181a2f42a.
10. Davis BM, Normando EM, Guo L, et al. Topical delivery of Avastin to the posterior segment of the eye in vivo using annexin A5-associated liposomes[J]. Small, 2014, 10(8): 1575-1584. DOI: 10.1002/smll.201303433.
11. Nomoto H, Shiraga F, Kuno N, et al. Pharmacokinetics of bevacizumab after topical, subconjunctival, and intravitreal administration in rabbits[J]. Invest Ophthalmol Vis Sci, 2009, 50(10): 4807-4813. DOI: 10.1167/iovs.08-3148.
12. Dastjerdi MH, Sadrai Z, Saban DR, et al. Corneal penetration of topical and subconjunctival bevacizumab[J]. Invest Ophthalmol Vis Sci, 2011, 52(12): 8718-8723. DOI: 10.1167/iovs.11-7871.
13. Moisseiev E, Waisbourd M, Ben-Artsi E, et al. Pharmacokinetics of bevacizumab after topical and intravitreal administration in human eyes[J]. Graefe’s Arch Clin Exp Ophthalmol, 2014, 252(2): 331-337. DOI: 10.1007/s00417-013-2495-0.
14. Sella R, Gal-Or O, Livny E, et al. Efficacy of topical aflibercept versus topical bevacizumab for the prevention of corneal neovascularization in a rat model[J]. Exp Eye Res, 2016, 146:224-232. DOI: 10.1016/j.exer.2016.03.021.
15. Motarjemizadeh Q, Aidenloo NS, Sepehri S. A comparative study of different concentrations of topical bevacizumab on the recurrence rate of excised primary pterygium: a short-term follow-up study[J]. Int Ophthalmol, 2016, 36(1): 63-71. DOI: 10.1007/s10792-015-0076-4.
16. Wang Y, Fei D, Vanderlaan M, et al. Biological activity of bevacizumab, a humanized anti-VEGF antibody in vitro[J]. Angio-genesis, 2004, 7(4): 335-345. DOI:10.1007/s10456-004-8272-2.

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Changes of intraocular drug concentration and pharmacokinetics of bevacizumab with annexin A5-associated liposome topically applied in the rabbit eyes

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