Intracameral Sustained-Release Bimatoprost Implant Delivers Bimatoprost to Target Tissues with Reduced Drug Exposure to Off-Target Tissues

Abstract

Purpose: To explore the ocular distribution of bimatoprost after intracameral administration of a biodegradable sustained-release bimatoprost implant (Bimatoprost SR) versus repeated topical administration of bimatoprost 0.03% ophthalmic solution in dogs. Bimatoprost SR and topical bimatoprost 0.03% previously were shown to have similar intraocular pressure-lowering effects in humans in a phase 1/2 clinical trial.Methods: Twenty-four beagle dogs received either once-daily topical bimatoprost 0.03% for 7 days or a bilateral intracameral administration of Bimatoprost SR (15 μg). At predetermined time points, ocular tissues were collected and concentrations of bimatoprost and bimatoprost acid were quantified using liquid chromatography–tandem mass spectrometry.Results: Bimatoprost SR administration enhanced delivery of study drug to a site of action [iris–ciliary body (ICB)] compared with topical bimatoprost (Cmax [bimatoprost+bimatoprost acid] = 18,200 and 4.13 ng/g, respectively). However, distribution of drug to tissues associated with prostaglandin analog (PGA)-related side effects (i.e., bulbar conjunctiva, eyelid margins, and periorbital fat) was limited following Bimatoprost SR administration (Cmax [bimatoprost+bimatoprost acid] = BLQ [beneath the limit of quantitation] to 0.354 ng/g) compared with topical dosing (Cmax [bimatoprost+bimatoprost acid] = 36.6–2,110 ng/g).Conclusions: Bimatoprost SR administration in dogs selectively delivered drug to the ICB with low or undetectable drug levels in ocular surface and extraocular tissues. Use of Bimatoprost SR for glaucoma treatment may reduce the incidence of adverse events typically associated with topical PGAs by targeting bimatoprost delivery to the key site of action of the PGA class and reducing exposure to off-target tissues.

Matrix Metalloproteinases and Glaucoma Treatment

“…The superimposed black and red arrows show for comparison the maximal iris-ciliary body bimatoprost plus bimatoprost acid concentrations obtained after topical bimatoprost treatment and Bimatoprost SR administration, respectively, in a drug distribution study in beagle dogs. 102 Bimatoprost SR, bimatoprost sustained-release implant; TIMP, tissue inhibitor of metalloproteinase. on the Novadur (Allergan plc, Dublin, Ireland) platform for drug delivery, which uses biodegradable polymers similar to those in biodegradable sutures and has demonstrated a long track record of safety with intraocular use.…”

“…Thus, >80% of drug is delivered to outflow tissues, whereas <5% of drug reaches intraocular tissues after topical administration of an eye drop. 101,102 The ability of Bimatoprost SR to provide targeted delivery of high bimatoprost concentrations to ocular outflow tissues was demonstrated in a drug distribution study using normotensive beagle dogs. 102 The time course of ocular drug concentrations after implant administration was consistent with the kinetics of drug release from the implant in vitro, where drug release is complete in less than 3 months: in the dog study, the implants had released 99.8% of their drug load and ocular tissue drug levels had significantly declined by 80 days after intracameral administration.…”

“…101,102 The ability of Bimatoprost SR to provide targeted delivery of high bimatoprost concentrations to ocular outflow tissues was demonstrated in a drug distribution study using normotensive beagle dogs. 102 The time course of ocular drug concentrations after implant administration was consistent with the kinetics of drug release from the implant in vitro, where drug release is complete in less than 3 months: in the dog study, the implants had released 99.8% of their drug load and ocular tissue drug levels had significantly declined by 80 days after intracameral administration. 102 Drug levels in ocular surface and periocular tissues such as the conjunctiva, eyelids, and periorbital fat were markedly reduced or undetectable after Bimatoprost SR 15 mg administration compared with 7 days of topical dosing with bimatoprost 0.03% ( Fig.…”

The future of canine glaucoma therapy

“…Intracameral implants include Bimatoprost SR (Allergan), ENV515 travoprost (Envisia Therapeutics, Inc), OTX‐TIC travoprost (Ocular Therapeutix, Inc), and iDose travoprost (Glaukos ® ) . Intracameral, biodegradable latanoprost‐, bimatoprost‐, and travoprost‐releasing devices have been tested successfully in normal dogs and dogs with POAG, but we are not aware of any plans to move these devices into veterinary clinical application . The use of ocular, slow‐releasing drug implants is not new in veterinary ophthalmology since cyclosporine devices are being used in both horses and dogs for recurrent uveitis, immune‐mediated keratitis, and keratoconjunctivitis sicca …”

“…39,41 Intracameral, biodegradable latanoprost-, bimatoprost-, and travoprost-releasing devices have been tested successfully in normal dogs and dogs with POAG, but we are not aware of any plans to move these devices into veterinary clinical application. [41][42][43][44] The use of ocular, slow-releasing drug implants is not new in veterinary ophthalmology since cyclosporine devices are being used in both horses and dogs for recurrent uveitis, immune-mediated keratitis, and keratoconjunctivitis sicca. [45][46][47] Our discussions on medical management of canine glaucoma also included the evaluation of compounds to decrease the rate of secondary glaucoma following phacoemulsification surgery.…”