Quantitative systems pharmacology of the eye: Tools and data for ocular QSP

Abstract

Good eyesight belongs to the most‐valued attributes of health, and diseases of the eye are a significant healthcare burden. Case numbers are expected to further increase in the next decades due to an aging society. The development of drugs in ophthalmology, however, is difficult due to limited accessibility of the eye, in terms of drug administration and in terms of sampling of tissues for drug pharmacokinetics (PKs) and pharmacodynamics (PDs). Ocular quantitative systems pharmacology models provide the opportunity to describe the distribution of drugs in the eye as well as the resulting drug‐response in specific segments of the eye. In particular, ocular physiologically‐based PK (PBPK) models are necessary to describe drug concentration levels in different regions of the eye. Further, ocular effect models using molecular data from specific cellular systems are needed to develop dose–response correlations. We here describe the current status of PK/PBPK as well as PD models for the eyes and discuss cellular systems, data repositories, as well as animal models in ophthalmology. The application of the various concepts is highlighted for the development of new treatments for postoperative fibrosis after glaucoma surgery.

Clinical Pharmacology Perspective on Development of Adeno‐Associated Virus Vector‐Based Retina Gene Therapy

“…Interestingly, progress has been made in the development of PBPK and QSP models for ocular delivery, in part due to advancement in current understanding of ocular physiology and transport processes, that can be used to describe both systemic and ocular distribution of the drug. 75 A semimechanistic model was developed in rabbits to study ocular PK of various proteins administered IVT; the model was used to estimate half-life in retina, vitreous and aqueous humor in relation to protein size up to a hydrodynamic radius of 14 nm, which is the minimum radius for monomeric AAVs, and the authors suggested that the half-life in each compartment (retina, vitreous, and aqueous humor) could be geometrically scaled to humans. 76 Network systems biology is another promising technique that has been used to study ophthalmic indications for which gene therapy products are being developed; for example, networks of gene regulation have been constructed in glaucoma 9 and AMD, [77][78][79] providing insights into the mechanisms underlying these multifactorial diseases, as well as used to identify the most effective proteins for retinal regeneration.…”

“…76 Network systems biology is another promising technique that has been used to study ophthalmic indications for which gene therapy products are being developed; for example, networks of gene regulation have been constructed in glaucoma 9 and AMD, [77][78][79] providing insights into the mechanisms underlying these multifactorial diseases, as well as used to identify the most effective proteins for retinal regeneration. 78 Moreover, by coupling network systems biology models with complex QSP models, 75 one could study the drug effects on the downstream disease pathway.…”

“…One approach proposed previously 28 is the use of PK‐PD models of transgene protein levels coupled with more complex QSP models of AAV biodistribution, transcription, and translation to characterize the processes from administration of the vector dose in the ocular compartment to pharmacological effect or clinical efficacy. Interestingly, progress has been made in the development of PBPK and QSP models for ocular delivery, in part due to advancement in current understanding of ocular physiology and transport processes, that can be used to describe both systemic and ocular distribution of the drug 75 . A semimechanistic model was developed in rabbits to study ocular PK of various proteins administered IVT; the model was used to estimate half‐life in retina, vitreous and aqueous humor in relation to protein size up to a hydrodynamic radius of 14 nm, which is the minimum radius for monomeric AAVs, and the authors suggested that the half‐life in each compartment (retina, vitreous, and aqueous humor) could be geometrically scaled to humans 76 .…”

Hypromellose in Ophthalmology

“…Примером успешной диффузии являются липофильные препараты, способные пассивно проходить через эпителий роговицы, но затем задерживающиеся благодаря барьерным свойствам гидрофильной стромы. Монослой эндотелия роговицы выступает в качестве клеточного барьера между стромой и водянистой влагой и также может модулировать степень проникновения лекарственных препаратов [7,12]. Дальнейшее распределение препарата, преодолевшего роговицу, происходит в водянистой влаге.…”

“…Многие местные лекарственные формы, содержащие НПВС, противоаллергические препараты, антибиотики, обладают в значительной степени гидрофильными свойствами, что ограничивает степень их проникновения в структуры глаза благодаря особенностям строения роговицы и конъюнктивы. Время местного воздействия препарата ограничивает оборот слезной пленки, что в итоге приводит к снижению концентрации действующего вещества в стекловидном теле и сетчатке [7].…”