In Vivo Pharmacokinetics of Bromfenac Ophthalmic Solution 0.075%, Bromfenac Ophthalmic Solution 0.07%, and Nepafenac/Amfenac Ophthalmic Suspension 0.3% in Rabbits

Overview

Journal Ophthalmol Ther

Specialty Ophthalmology

Date 2018 May 16

PMID 29761367

Citations 5

Authors

John D Sheppard

Paul C Cockrum

Angela Justice

Mark C Jasek

Affiliations

Soon will be listed here.

Abstract

Introduction: Little is known of the ocular distribution characteristics of currently branded non-steroidal anti-inflammatory drugs (NSAIDs) in the United States. This study was designed to predict the ocular bioavailability characteristics in humans using Dutch Belted rabbits as a surrogate. Commercially available, topically-applied NSAIDs containing bromfenac or nepafenac/amfenac were evaluated.

Methods: 126 healthy adult Dutch Belted rabbits were randomly assigned to three treatment cohorts (BromSite twice daily [BID] in the right eye, BromSite once daily [QD] in the right eye, Prolensa QD in the right eye and Ilevro™ QD in the left eye) and 7 post-dosing time points (0.5, 1, 2, 4, 8, 12, 24 h after final instillation). The study eyes received 40 µL of the assigned drug for a consecutive 9 days. Samples of aqueous humor, iris-ciliary body, choroid, sclera, and retina were harvested from the study eyes at the assigned time point after the last dose on the 9th day. NSAID content in ocular tissues was analyzed using high-performance liquid chromatography (HPLC), and area under the curve (AUC), maximum concentration (C), and time to maximum concentration (T) were determined.

Results: Peak NSAID concentrations were reached within 1-3 h in the anterior segment and within 1-3 h in the posterior segment after last dose. Throughout the ocular tissues, both AUC and C for BromSite (BID and QD) were consistently higher than respective NSAID concentrations of Prolensa QD and Ilevro QD. When comparing BromSite BID to QD, the BID regimen produced generally higher but statistically similar bromfenac concentrations throughout the ocular tissues except in the aqueous humor and iris-ciliary body, where the AUC BID was statistically significantly higher with BromSite BID.

Conclusion: As a surrogate to human ocular bioavailability, BromSite demonstrated significantly greater NSAID compared to Prolensa QD and Ilevro QD. The DuraSite component of BromSite appears to enhance ocular penetration throughout both anterior and posterior tissues.

Funding: Sun Pharmaceutical Industries Ltd.

Citing Articles

Topical bromfenac in VEGF-driven maculopathies: topical review and meta-analysis.

Kulikov A, Vasiliev A, Kalinicheva Y, Maltsev D BMC Ophthalmol. 2024; 24(1):369.

PMID: 39180057 PMC: 11344392. DOI: 10.1186/s12886-024-03650-z.

Binary Polymeric Surfactant Mixtures for the Development of Novel Loteprednol Etabonate Nanomicellar Eyedrops.

Tampucci S, Monti D, Burgalassi S, Terreni E, Paganini V, Di Gangi M Pharmaceuticals (Basel). 2023; 16(6).

PMID: 37375811 PMC: 10305198. DOI: 10.3390/ph16060864.

Biopharmaceutics of Topical Ophthalmic Suspensions: Importance of Viscosity and Particle Size in Ocular Absorption of Indomethacin.

Toropainen E, Fraser-Miller S, Novakovic D, Del Amo E, Vellonen K, Ruponen M Pharmaceutics. 2021; 13(4).

PMID: 33810564 PMC: 8067094. DOI: 10.3390/pharmaceutics13040452.

Use of topical bromfenac for treating ocular pain and inflammation beyond cataract surgery: a review of published studies.

Schechter B Clin Ophthalmol. 2019; 13:1439-1460.

PMID: 31534309 PMC: 6682171. DOI: 10.2147/OPTH.S208700.

An ex vivo human aqueous humor-concentration comparison of two commercial bromfenac formulations.

Walters T, Smyth-Medina R, Cockrum P Clin Ophthalmol. 2018; 12:943-947.

PMID: 29849449 PMC: 5967376. DOI: 10.2147/OPTH.S170540.

References

Abel Jr R, Abel A . Perioperative antibiotic, steroidal, and nonsteroidal anti-inflammatory agents in cataract intraocular lens surgery. Curr Opin Ophthalmol. 1996; 7(1):39-42. DOI: 10.1097/00055735-199602000-00008. View

Walters T, Raizman M, Ernest P, Gayton J, Lehmann R . In vivo pharmacokinetics and in vitro pharmacodynamics of nepafenac, amfenac, ketorolac, and bromfenac. J Cataract Refract Surg. 2007; 33(9):1539-45. DOI: 10.1016/j.jcrs.2007.05.015. View

Jones B, Neville M . Nepafenac: an ophthalmic nonsteroidal antiinflammatory drug for pain after cataract surgery. Ann Pharmacother. 2013; 47(6):892-6. DOI: 10.1345/aph.1R757. View

Kida T, Kozai S, Takahashi H, Isaka M, Tokushige H, Sakamoto T . Pharmacokinetics and efficacy of topically applied nonsteroidal anti-inflammatory drugs in retinochoroidal tissues in rabbits. PLoS One. 2014; 9(5):e96481. PMC: 4010472. DOI: 10.1371/journal.pone.0096481. View

Kim S, Schoenberger S, Thorne J, Ehlers J, Yeh S, Bakri S . Topical Nonsteroidal Anti-inflammatory Drugs and Cataract Surgery: A Report by the American Academy of Ophthalmology. Ophthalmology. 2015; 122(11):2159-68. DOI: 10.1016/j.ophtha.2015.05.014. View

DuBois R, Abramson S, Crofford L, Gupta R, Simon L, van de Putte L . Cyclooxygenase in biology and disease. FASEB J. 1998; 12(12):1063-73. View

Raizman M . Corticosteroid therapy of eye disease. Fifty years later. Arch Ophthalmol. 1996; 114(8):1000-1. DOI: 10.1001/archopht.1996.01100140208016. View

Masferrer J, Kulkarni P . Cyclooxygenase-2 inhibitors: a new approach to the therapy of ocular inflammation. Surv Ophthalmol. 1997; 41 Suppl 2:S35-40. DOI: 10.1016/s0039-6257(97)80005-7. View

Sheppard J . Topical bromfenac for prevention and treatment of cystoid macular edema following cataract surgery: a review. Clin Ophthalmol. 2016; 10:2099-2111. PMC: 5087782. DOI: 10.2147/OPTH.S86971. View

10.

Bonazzi A, Mastyugin V, Mieyal P, Dunn M . Regulation of cyclooxygenase-2 by hypoxia and peroxisome proliferators in the corneal epithelium. J Biol Chem. 2000; 275(4):2837-44. DOI: 10.1074/jbc.275.4.2837. View

11.

Walsh D, Moran H, Shamblee D, Uwaydah I, Welstead Jr W, SANCILIO L . Antiinflammatory agents. 3. Synthesis and pharmacological evaluation of 2-amino-3-benzoylphenylacetic acid and analogues. J Med Chem. 1984; 27(11):1379-88. DOI: 10.1021/jm00377a001. View

12.

Ahuja M, Dhake A, Sharma S, Majumdar D . Topical ocular delivery of NSAIDs. AAPS J. 2008; 10(2):229-41. PMC: 2751374. DOI: 10.1208/s12248-008-9024-9. View

13.

Shafiee A, Bowman L, Hou E, Hosseini K . Aqueous humor penetration of ketorolac formulated in DuraSite or DuraSite 2 delivery systems compared to Acular LS in rabbits. J Ocul Pharmacol Ther. 2013; 29(9):812-6. DOI: 10.1089/jop.2013.0016. View

14.

Oka T, Shearer T, Azuma M . Involvement of cyclooxygenase-2 in rat models of conjunctivitis. Curr Eye Res. 2004; 29(1):27-34. DOI: 10.1080/02713680490513164. View

15.

Si E, Bowman L, Hosseini K . Pharmacokinetic comparisons of bromfenac in DuraSite and Xibrom. J Ocul Pharmacol Ther. 2011; 27(1):61-6. DOI: 10.1089/jop.2010.0103. View

16.

Colin J . The role of NSAIDs in the management of postoperative ophthalmic inflammation. Drugs. 2007; 67(9):1291-308. DOI: 10.2165/00003495-200767090-00004. View

17.

Schalnus R . Topical nonsteroidal anti-inflammatory therapy in ophthalmology. Ophthalmologica. 2003; 217(2):89-98. DOI: 10.1159/000068563. View

18.

Guex-Crosier Y . [Non-steroidal anti-inflammatory drugs and ocular inflammation]. Klin Monbl Augenheilkd. 2001; 218(5):305-8. DOI: 10.1055/s-2001-15886. View

19.

Baklayan G, Patterson H, Song C, Gow J, McNamara T . 24-hour evaluation of the ocular distribution of (14)C-labeled bromfenac following topical instillation into the eyes of New Zealand White rabbits. J Ocul Pharmacol Ther. 2008; 24(4):392-8. DOI: 10.1089/jop.2007.0082. View