Ocular Pharmacokinetics of Brimonidine Drug Delivery System in Monkeys and Translational Modeling for Selection of Dose and Frequency in Clinical Trials.

Mitalee Tamhane,Mayssa Attar,Kenneth T Luu

doi:10.1124/jpet.120.000483

Mitalee Tamhane, Mayssa Attar + Show 1 more

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https://doi.org/10.1124/jpet.120.000483

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Abstract

Brimonidine, a selective α 2-adrenoceptor agonist, displays putative retinal cyto- and neuroprotective activity in vitro and in vivo. An intravitreal sustained-release brimonidine implant, Brimonidine Posterior Segment Drug Delivery System (brimonidine DDS), allowing targeted drug delivery to the retina has been developed for potential clinical application. This study evaluates the in vivo posterior segment pharmacokinetics of brimonidine DDS implant in the monkey eye and applies translational pharmacokinetic modeling to predict tissue exposure in the human eye. Anesthetized cynomolgus monkeys received a single intravitreal injection of brimonidine DDS 400 µg implant before removal of study eyes at days 7, 30, 60, 92, 120, and 150 postimplant (three to four animals per time point) for assay of brimonidine in aqueous humor, vitreous, and retina samples. Brimonidine concentrations in the human eye were modeled using a linear, three-compartment model assuming bidirectional distribution to/from the aqueous humor and retina and elimination from the aqueous humor. Monkey tissue volumes were scaled up to human values; intercompartmental and elimination rate constants were assumed to be identical in the two species. Modeling and simulations were performed using NONMEM v. 7.3, R 3.5.1. Brimonidine exposure was highest in the monkey vitreous and retina; concentrations in the central (macula) and peripheral retina were maintained at high levels (>100 ng/g) for 3 to 4 months. Simulated brimonidine concentration-time profiles in human macula indicated that brimonidine DDS 400 µg implant would deliver effective drug concentrations (20.7‒82.2 ng/g, based on animal pharmacology) for approximately 3 months. Accordingly, administration of the 400 µg implant at 3-month intervals is recommended. SIGNIFICANCE STATEMENT: Brimonidine, an α 2-adrenoceptor agonist, is cyto- and neuroprotective in animal models of retinal/optic nerve injury. Brimonidine Posterior Segment Drug Delivery System (brimonidine DDS) is an intravitreal sustained-release implant with potential ophthalmological applications. This study explores the pharmacokinetics of brimonidine DDS 400 µg implant in the monkey eye and uses compartmental modeling to predict human ocular tissue exposure. Targeted retinal brimonidine delivery from vitreous was demonstrated in monkeys. Simulated tissue concentration-time profiles indicated persistence of pharmacologically effective brimonidine concentrations for ≈3 months in human retina.

Highlights

Brimonidine is a highly selective a2-adrenergic receptor agonist that is currently approved in the United States and Europe for the treatment of open-angle glaucoma and ocular hypertension
Systemic drug exposure was negligible after intravitreal administration of brimonidine Brimonidine Posterior Segment Drug Delivery System (DDS) 400 mg implant, with plasma brimonidine concentrations remaining below the limit of quantification (0.05 ng/ml) at all time points
Intravitreal injection is a widely accepted route of administration for ensuring targeted drug delivery to the posterior segment of the eye. This route is approved for administration of anti–vascular endothelial growth factor therapy for choroidal neovascularization caused by “wet” age-related macular degeneration and for corticosteroid treatments for intraocular inflammation (Novack, 2009)

Summary

Introduction

Brimonidine is a highly selective a2-adrenergic receptor agonist that is currently approved in the United States and Europe for the treatment of open-angle glaucoma and ocular hypertension. In addition to its intraocular pressure–lowering effect, experimental studies have demonstrated that brimonidine possesses cyto- and neuroprotective activity in a variety of animal models of retinal and optic nerve injury, including. All authors are current or former full-time employees and stockholders of AbbVie, Inc. acute retinal ischemia (Donello et al, 2001; Lafuente et al, 2001; Vidal-Sanz et al, 2001; Lai et al, 2002), excitotoxic retinal injury (Galindo-Romero et al, 2016), blue light phototoxicity (Ortın-Martınez et al, 2014; Valiente-Soriano et al, 2019), chronic ocular hypertension (WoldeMussie et al, 2001; Hernandez et al, 2008), and optic nerve crush (Yoles et al, 1999; Saylor et al, 2009). Research indicates that the a2-adrenergic receptor is expressed throughout

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