Abstract
Intravitreal (IVT) injection of pharmacological agents is an established and widely used procedure for the treatment of many posterior segment of the eye diseases. IVT injections permit drugs to reach high concentrations in the retina whilst limiting systemic exposure. Beyond the risk of secondary complications such as intraocular infection, the potential of systemic adverse events cannot be neglected. Therefore, a detailed understanding of the rules governing systemic exposure following IVT drug administration remains a prerequisite for the evaluation and development of new pharmacological agents intended for eye delivery. We present here a novel mathematical model to describe and predict circulating drug levels following IVT in the rabbit eye, a species which is widely used for drug delivery, pharmacokinetic, and pharmacodynamic studies. The mathematical expression was derived from a pharmacokinetic model that assumes the existence of a compartment between the vitreous humor compartment itself and the systemic compartment. We show that the model accurately describes circulating levels of THR-149, a plasma kallikrein inhibitor in development for the treatment of diabetic macular edema. We hypothesize that the model based on the rabbit eye has broader relevance to the human eye and can be used to analyze systemic exposure of a variety of drugs delivered in the eye.
Highlights
In recent years, intravitreal (IVT) injection has become the preferred administration route of pharmacological agents for the treatment of the back of the eye diseases such as age-related macular degeneration and diabetic retinopathy
We present here a novel mathematical model to describe and predict circulating drug levels following IVT in the rabbit eye, a species which is widely used for drug delivery, pharmacokinetic, and pharmacodynamic studies
We hypothesize that the model based on the rabbit eye has broader relevance to the human eye and can be used to analyze systemic exposure of a variety of drugs delivered in the eye
Summary
Intravitreal (IVT) injection has become the preferred administration route of pharmacological agents for the treatment of the back of the eye diseases such as age-related macular degeneration and diabetic retinopathy. The systemic risk is well illustrated by the commonly used anti-VEGF agents which IVT administration is suspected to be associated with increased risk for ischemic cerebrovascular disease, thromboembolic events, non-ocular hemorrhagic events, nephrotoxicity, acute blood pressure elevations, serious systemic infections, gastrointestinal disorders, and even mortality. This is a low but consistent risk and limiting the bioavailability of systemic VEGF could be detrimental for vascular integrity, especially in patients with retinal disease who are at risk for cardiovascular diseases [3,4,5,6,7]
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