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Preclinical challenges for developing long acting intravitreal medicines

Awwad, S; Henein, C; Ibeanu, N; Khaw, PT; Brocchini, S; (2020) Preclinical challenges for developing long acting intravitreal medicines. European Journal of Pharmaceutics and Biopharmaceutics 10.1016/j.ejpb.2020.05.005. (In press).

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Abstract

The majority of blinding conditions arise due to chronic pathologies in the retina. During the last two decades, antibody-based medicines administered by intravitreal injection directly into the back of the eye have revolutionised the treatment of chronic retinal diseases characterised by uncontrolled blood vessel growth, e.g. wet age-related macular degeneration (wAMD), diabetic retinopathy (DR) and choroidal neovascularisation. Although intravitreal injections have become a commonly performed ophthalmic procedure that provides a reproducible dose to maximise drug exposure in the back of the eye, there is a need to minimise the frequency and cumulative number of intravitreal injections. Developing longer-acting intraocular therapies is one key strategy that is being pursued. Pharmaceutical preclinical development of intraocular medicines is heavily reliant on the use of animal models to determine ocular tolerability, pharmacokinetics, biodistribution and drug stability. Animal eyes are different from human eyes, such as the anatomy, organisation of vitreous macromolecular structure, aqueous outflow and immune response; all which impacts the ability to translate preclinical data into a clinical product. The development of longer acting protein formulations using animals is also limited because animals reject human proteins. Preclinical strategies also do not account for differences in the vitreous due to ageing and whether a vitrectomy has been performed. Intraocular formulations must reside and clear from the vitreous body, so there is a need for the formulation scientist to have knowledge about vitreous structure and physiology to facilitate preclinical development strategies. Preclinical pharmaceutical development paradigms used to create therapies for other routes of administration (e.g. oral and intravenous) are grounded on the use of preclinical in vitro models. Analogous pharmaceutical strategies with appropriately designed in vitro models that can account for intraocular mass transfer to estimate pharmacokinetic profiles can be used to develop in vitro-in vivo correlations (IVIVCs) to accelerate the preclinical optimisation of long acting intraocular formulations. Data can then inform preclinical in vivo and clinical studies. With the now widespread use of intravitreal injections, it has also important early in preclinical studies to ensure there is a viable regulatory pathway for new therapies. Knowledge of these factors will help in the development of long acting intravitreal medicines, which is rapidly evolving into a distinct pharmaceutical discipline.

Type: Article
Title: Preclinical challenges for developing long acting intravitreal medicines
DOI: 10.1016/j.ejpb.2020.05.005
Publisher version: https://doi.org/10.1016/j.ejpb.2020.05.005
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: vitreous, pharmacokinetics, drug delivery, ocular, posterior segment, intravitreal
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Education
UCL > Provost and Vice Provost Offices > School of Education > UCL Institute of Education
UCL > Provost and Vice Provost Offices > School of Education > UCL Institute of Education > Centre for Languages and Intl Educatn
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > Institute of Ophthalmology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy > Pharmaceutics
URI: https://discovery.ucl.ac.uk/id/eprint/10098066
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