Systemic exposure following intravitreal administration of therapeutic agents: an integrated pharmacokinetic approach. 1. THR-149.

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.

Systemic exposure following intravitreal administration of therapeutic agents: an integrated pharmacokinetic approach. 2. THR-687.

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.

Inversion of the 3D exponential x-ray transform for a half equatorial band and other semi-circular geometries.

This work presents new mathematical results on the inversion of the exponential x-ray transform. It is shown that a reconstruction formula can be obtained for any dataset whose projection directions consist of a union of half great circles on the unit sphere. A basic example of such a dataset is the semi-equatorial band. The discussion in the paper is mostly focused on this example. The reconstruction formula takes the form of a Neumann (geometric) series and is both exact and stable. The exponential x-ray transform has been mainly studied in SPECT imaging. In this context, our results demonstrate mathematically that fully 3D image reconstruction in SPECT with non-zero attenuation does not always require symmetric datasets (opposing views).