Topical Solution for Retinal Delivery: Bevacizumab and Ranibizumab Eye Drops in Anti-Aggregation Formula (AAF) in Rabbits

Overview

Journal Pharm Res

Specialties Pharmacology
Pharmacy

Date 2024 Jun 5

PMID 38839719

Authors

Steven A Giannos

Edward R Kraft

Jonathan D Luisi

Mary E Schmitz-Brown

Valentina Reffatto

Kevin H Merkley

Praveena K Gupta

Affiliations

Soon will be listed here.

Abstract

Purpose: Wet age-related macular degeneration (AMD) is a blinding retinal disease. Monthly intravitreal anti-VEGF antibody injections of bevacizumab (off-label) and ranibizumab (FDA approved) are the standard of care. Antibody aggregation may interfere with ocular absorption/distribution. This study assessed topical delivery of dilute antibodies to the posterior segment of rabbit eyes using a novel anti-aggregation formula (AAF).

Methods: Bevacizumab, or biosimilar ranibizumab was diluted to 5 mg/ml in AAF. All rabbits were dosed twice daily. Substudy 1 rabbits (bevacizumab, 100 µl eye drops): Group 1 (bevacizumab/AAF, n = 6); Group 2 (bevacizumab/PBS, n = 7) and Vehicle control (AAF, n = 1). Substudy 2 rabbits (ranibizumab biosimilar/AAF, 50 µl eye drops): (ranibizumab biosimilar/AAF, n = 8). At 14.5 days, serum was drawn from rabbits. Aqueous, vitreous and retina samples were recovered from eyes and placed into AAF aliquots. Tissue analyzed using AAF as diluent.

Results: Bevacizumab in AAF permeated/accumulated in rabbit aqueous, vitreous and retina 10 times more, than when diluted in PBS. AAF/0.1% hyaluronic acid eye drops, dosed twice daily, provided mean tissue concentrations (ng/g) in retina (29.50), aqueous (12.34), vitreous (3.46), and serum (0.28 ng/ml). Additionally, the highest concentration (ng/g) of ranibizumab biosimilar was present in the retina (18.0), followed by aqueous (7.82) and vitreous (1.47). Serum concentration was negligible (< 0.04 ng/ml). No irritation was observed throughout the studies.

Conclusions: Bevacizumab and ranibizumab, in an AAF diluent eye drop, can be delivered to the retina, by the twice daily dosing of a low concentration mAb formulation. This may prove to be an adjunct to intravitreal injections.

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References

Ambati J, Atkinson J, Gelfand B . Immunology of age-related macular degeneration. Nat Rev Immunol. 2013; 13(6):438-51. PMC: 3941009. DOI: 10.1038/nri3459. View

Kovach J, Schwartz S, Flynn Jr H, Scott I . Anti-VEGF Treatment Strategies for Wet AMD. J Ophthalmol. 2012; 2012:786870. PMC: 3317200. DOI: 10.1155/2012/786870. View

Stewart M . The expanding role of vascular endothelial growth factor inhibitors in ophthalmology. Mayo Clin Proc. 2012; 87(1):77-88. PMC: 3498409. DOI: 10.1016/j.mayocp.2011.10.001. View

Weber M, Sennlaub F, Souied E, Cohen S, Behar-Cohen F, Milano G . [Review and expert opinion in age related macular degeneration. Focus on the pathophysiology, angiogenesis and pharmacological and clinical data]. J Fr Ophtalmol. 2014; 37(7):566-79. DOI: 10.1016/j.jfo.2014.06.001. View

Eandi C, Alovisi C, de Sanctis U, Grignolo F . Treatment for neovascular age related macular degeneration: The state of the art. Eur J Pharmacol. 2016; 787:78-83. DOI: 10.1016/j.ejphar.2016.03.002. View

Del Amo E, Rimpela A, Heikkinen E, Kari O, Ramsay E, Lajunen T . Pharmacokinetic aspects of retinal drug delivery. Prog Retin Eye Res. 2016; 57:134-185. DOI: 10.1016/j.preteyeres.2016.12.001. View

Bakri S, Snyder M, Reid J, Pulido J, Ezzat M, Singh R . Pharmacokinetics of intravitreal ranibizumab (Lucentis). Ophthalmology. 2007; 114(12):2179-82. DOI: 10.1016/j.ophtha.2007.09.012. View

Ghasemi Falavarjani K, Nguyen Q . Adverse events and complications associated with intravitreal injection of anti-VEGF agents: a review of literature. Eye (Lond). 2013; 27(7):787-94. PMC: 3709385. DOI: 10.1038/eye.2013.107. View

Nayak K, Misra M . A review on recent drug delivery systems for posterior segment of eye. Biomed Pharmacother. 2018; 107:1564-1582. DOI: 10.1016/j.biopha.2018.08.138. View

10.

Pescina S, Ferrari G, Govoni P, Macaluso C, Padula C, Santi P . In-vitro permeation of bevacizumab through human sclera: effect of iontophoresis application. J Pharm Pharmacol. 2010; 62(9):1189-94. DOI: 10.1111/j.2042-7158.2010.01153.x. View

11.

Suen W, Wong H, Yu Y, Lau L, Lo A, Chau Y . Ultrasound-mediated transscleral delivery of macromolecules to the posterior segment of rabbit eye in vivo. Invest Ophthalmol Vis Sci. 2013; 54(6):4358-65. DOI: 10.1167/iovs.13-11978. View

12.

Gote V, Sikder S, Sicotte J, Pal D . Ocular Drug Delivery: Present Innovations and Future Challenges. J Pharmacol Exp Ther. 2019; 370(3):602-624. DOI: 10.1124/jpet.119.256933. View

13.

Li S, Liddell M, Wen H . Effective electrophoretic mobilities and charges of anti-VEGF proteins determined by capillary zone electrophoresis. J Pharm Biomed Anal. 2011; 55(3):603-7. PMC: 3070845. DOI: 10.1016/j.jpba.2010.12.027. View

14.

Wen H, Hao J, Li S . Characterization of human sclera barrier properties for transscleral delivery of bevacizumab and ranibizumab. J Pharm Sci. 2012; 102(3):892-903. PMC: 3787849. DOI: 10.1002/jps.23387. View

15.

Hutton-Smith L, Gaffney E, Byrne H, Maini P, Schwab D, Mazer N . A Mechanistic Model of the Intravitreal Pharmacokinetics of Large Molecules and the Pharmacodynamic Suppression of Ocular Vascular Endothelial Growth Factor Levels by Ranibizumab in Patients with Neovascular Age-Related Macular Degeneration. Mol Pharm. 2016; 13(9):2941-50. DOI: 10.1021/acs.molpharmaceut.5b00849. View

16.

Hirvonen L, Fruhwirth G, Srikantha N, Barber M, Neffendorf J, Suhling K . Hydrodynamic Radii of Ranibizumab, Aflibercept and Bevacizumab Measured by Time-Resolved Phosphorescence Anisotropy. Pharm Res. 2016; 33(8):2025-32. PMC: 4942501. DOI: 10.1007/s11095-016-1940-2. View

17.

Giannos S, Kraft E, Zhao Z, Merkley K, Cai J . Formulation Stabilization and Disaggregation of Bevacizumab, Ranibizumab and Aflibercept in Dilute Solutions. Pharm Res. 2018; 35(4):78. PMC: 5830485. DOI: 10.1007/s11095-018-2368-7. View

18.

Giannos S, Kraft E, Zhao Z, Merkley K, Cai J . Photokinetic Drug Delivery: Near infrared (NIR) Induced Permeation Enhancement of Bevacizumab, Ranibizumab and Aflibercept through Human Sclera. Pharm Res. 2018; 35(6):110. PMC: 5876416. DOI: 10.1007/s11095-018-2392-7. View

19.

Campbell M, Humphries M, Humphries P . Barrier modulation in drug delivery to the retina. Methods Mol Biol. 2012; 935:371-80. DOI: 10.1007/978-1-62703-080-9_26. View

20.

Doguizi S, Sekeroglu M, Inanc M, Anayol M, Yilmazbas P . Evaluation of pain during intravitreal aflibercept injections. Eur J Ophthalmol. 2017; 28(1):63-67. DOI: 10.5301/ejo.5001001. View