title: The PK-Eye: A Novel In Vitro Ocular Flow Model for Use in Preclinical Drug Development.
abstract: A 2-compartment in vitro eye flow model has been developed to estimate ocular drug clearance by the anterior aqueous outflow pathway. The model is designed to accelerate the development of longer-acting ophthalmic therapeutics. Dye studies show aqueous flow is necessary for a molecule injected into the vitreous cavity to clear from the model. The clearance times of proteins can be estimated by collecting the aqueous outflow, which was first conducted with bevacizumab using phosphate-buffered saline in the vitreous cavity. A simulated vitreous solution was then used and ranibizumab (0.5 mg) displayed a clearance time of 8.1 ± 3.1 days, which is comparable to that observed in humans. The model can estimate drug release from implants or the dissolution of suspensions as a first step in their clearance mechanism, which will be the rate-limiting step for the overall resident time of a candidate dosage form in the vitreous. A suspension of triamcinolone acetonide (Kenalog®) (4.0 mg) displayed clearance times spanning 26-28 days. These results indicate that the model can be used to determine in vitro-in vivo correlations in preclinical studies to develop long-lasting therapeutics to treat blinding diseases at the back of the eye.
authors.affiliation: National Institute for Health Research (NIHR) Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, London, EC1V 9EL, United Kingdom.|UCL School of Pharmacy, London, WC1N 1AX, United Kingdom.
authors.forename: Sahar
authors.initials: S
authors.lastname: Awwad
authors.affiliation: National Institute for Health Research (NIHR) Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, London, EC1V 9EL, United Kingdom.|UCL School of Pharmacy, London, WC1N 1AX, United Kingdom.
authors.forename: Alastair
authors.initials: A
authors.lastname: Lockwood
authors.affiliation: National Institute for Health Research (NIHR) Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, London, EC1V 9EL, United Kingdom.|UCL School of Pharmacy, London, WC1N 1AX, United Kingdom.
authors.forename: Steve
authors.initials: S
authors.lastname: Brocchini
authors.affiliation: National Institute for Health Research (NIHR) Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, London, EC1V 9EL, United Kingdom.
authors.forename: Peng T
authors.initials: PT
authors.lastname: Khaw
mesh_terms: D000418:Albumins / Q000378:metabolism; D001082:Aqueous Humor / Q000378:metabolism*; D000068258:Bevacizumab / Q000493:pharmacokinetics; D016503:Drug Delivery Systems; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D005128:Eye Diseases / Q000188:drug therapy; D006801:Humans; D058449:Intravitreal Injections; D008954:Models, Biological; D009883:Ophthalmic Solutions; D010599:Pharmacokinetics; D015203:Reproducibility of Results; D014222:Triamcinolone Acetonide / Q000493:pharmacokinetics; D014783:Viscosity; D014822:Vitreous Body / Q000378:metabolism
chemical_list: D000418:Albumins; D009883:Ophthalmic Solutions; D000068258:Bevacizumab; D014222:Triamcinolone Acetonide
keywords: Intraocular fluid flow; in vitro model; in vitro/in vivo correlations (IVIVC); intraocular drug suspension; intravitreal injection; ocular drug delivery; pharmacokinetics; protein delivery; proteins