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Systemic exposure following intravitreal administration of therapeutic agents: an integrated pharmacokinetic approach. 2. THR-687
- Source :
- Vanhove, M, Wagner, J-M, Noppen, B, Jonckx, B, Vermassen, E & Stitt, A W 2021, ' Systemic exposure following intravitreal administration of therapeutic agents: an integrated pharmacokinetic approach. 2. THR-687 ', Journal of Pharmacokinetics and Pharmacodynamics . https://doi.org/10.1007/s10928-021-09774-9, Journal of Pharmacokinetics and Pharmacodynamics
- Publication Year :
- 2021
-
Abstract
- Intravitreal (IVT) injection remains the preferred administration route of pharmacological agents intended for the treatment of back of the eye diseases such as diabetic macular edema (DME) and neovascular age-related macular degeneration (nvAMD). The procedure enables drugs to be delivered locally at high concentrations whilst limiting whole body exposure and associated risk of systemic adverse events. Nevertheless, intravitreally-delivered drugs do enter the general circulation and achieving an accurate understanding of systemic exposure is pivotal for the evaluation and development of drugs administered in the eye. We report here the full pharmacokinetic properties of THR-687, a pan RGD integrin antagonist currently in clinical development for the treatment of DME, in both rabbit and minipig. Pharmacokinetic characterization included description of vitreal elimination, of systemic pharmacokinetics, and of systemic exposure following IVT administration. For the latter, we present a novel pharmacokinetic model that assumes clear partition between the vitreous humor compartment itself where the drug is administered and the central systemic compartment. We also propose an analytical solution to the system of differential equations that represent the pharmacokinetic model, thereby allowing data analysis with standard nonlinear regression analysis. The model accurately describes circulating levels of THR-687 following IVT administration in relevant animal models, and we suggest that this approach is relevant to a range of drugs and analysis of subsequent systemic exposure.
- Subjects :
- Drug
genetic structures
Swine
media_common.quotation_subject
Diabetic macular edema
Pharmacology
Macular Edema
03 medical and health sciences
0302 clinical medicine
Pharmacokinetics
SDG 3 - Good Health and Well-being
Animals
Medicine
Adverse effect
media_common
Integrated pharmacokinetics
Original Paper
Diabetic Retinopathy
business.industry
Integrin antagonist
Intravitreal administration
Macular degeneration
medicine.disease
eye diseases
Vitreous Body
General Circulation Model
Intravitreal Injections
030221 ophthalmology & optometry
Swine, Miniature
Rabbits
Systemic exposure
business
030217 neurology & neurosurgery
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- Vanhove, M, Wagner, J-M, Noppen, B, Jonckx, B, Vermassen, E & Stitt, A W 2021, ' Systemic exposure following intravitreal administration of therapeutic agents: an integrated pharmacokinetic approach. 2. THR-687 ', Journal of Pharmacokinetics and Pharmacodynamics . https://doi.org/10.1007/s10928-021-09774-9, Journal of Pharmacokinetics and Pharmacodynamics
- Accession number :
- edsair.doi.dedup.....13bd9d4645464232f62949578a1152af