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Norman Alan Mazer, Laurence A. Hutton-Smith, Helen M. Byrne, Eamonn A. Gaffney, Philip K. Maini, Kapil Gadkar; What Determines the Retinal Concentration of an Intravitreally Injected Antibody? New Insights Using a 3-Compartment Semi-Mechanistic Pharmacokinetic Model. Invest. Ophthalmol. Vis. Sci. 2017;58(8):905.
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© ARVO (1962-2015); The Authors (2016-present)
Antibodies and antibody fragments injected intravitreally (IVT) for the treatment of neovascular AMD must permeate through the inner limiting membrane (ILM) into the retina and through the retinal pigment epithelium (RPE) to enter the choroid. A quantitative understanding of the determinants of retinal permeation, concentration and elimination is important for new drug development. We present a semi-mechanistic, 3-compartment pharmacokinetic (PK) model to describe the antibody concentrations in the retina, vitreous and aqueous compartments following a single IVT injection.
The 3-compartment model is expressed using ordinary first-order differential equations. Transfer between the vitreous and retina is dependent on the permeability of the ILM (PILM). Elimination from retina to choroid is dependent on the permeability of the RPE (PRPE). The key ocular PK parameters were estimated for Fab, Fc, IgG and IgG null molecules by fitting the model to experimental data obtained in the rabbit (Gadkar K et al., IOVS 2015: 56; 5390-5400).
The model predicts that the ocular half-life, t1/2, will be the same for all 3 compartments. It increases from 3.1 to 5.4 days in proportion to the hydrodynamic radius (Rh) of the molecules, which ranges from 2.5 (Fab) to 4.9 (IgG) nm. Estimates of PILM and PRPE for the rabbit retina are comparable to each other, decrease with Rh, and are in good agreement with ex-vivo permeability measurements from bovine retina. The model predicts that the vitreous-to-retina concentration ratio is approximately equal to 1+PRPE/PILM; consistent with the experimentally observed concentration ratios for IgG (~2.1) and Fab (~2.4). The model further suggests that approximately 80-90% of the IVT dose will be eliminated via the aqueous humor vs. 10-20% via the retina/choroid. Extrapolating our analysis to very large macromolecules, e.g., adeno-associated virus (AAV) nanoparticles (Rh = 14 nm), we predict very low permeability values that would appreciably limit retinal permeation.
Our semi-mechanistic model provides a novel quantitative framework for interpreting ocular PK and the effects of molecule size on rate-determining parameters. The permeability estimates derived in the rabbit may be useful for estimating retinal drug concentrations in the human eye.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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