A physiologically based pharmacokinetic model to describe [89Zr]Zr-DFO-Adalimumab specific activity after intravitreal administration to rats with endotoxin-induced uveitis.

Despite new biologic drugs have been developed to change the course of ocular disorders, the delivery and quantification of drug exposure in the eye remains as a critical challenge. This work aimed to develop a physiologically based pharmacokinetic (PBPK) model of [89Zr]Zr-DFO-Adalimumab after intravitreal (IVT) administration in healthy and endotoxin-induced uveitis (EIU) diseased rats to assess the effect of dose on TNF-α reduction in the anterior chamber of the eye. A full PBPK model considering both eyes and cervical lymph nodes was created in PK-Sim®/MoBi®. A temporal increase in intraocular flows because of the reversible increase in intraocular pressure after IVT administration was also implemented. Disease model incorporated reversible physiopathological changes related to anterior uveitis such as breakdown of blood-aqueous barrier, iritis, increased TNF-α synthesis and ocular hypotony. The PBPK model was ultimately used to assess the effect of IVT administered adalimumab on TNF-α kinetics in anterior chamber of the eye at 0.019, 0.038, 0.095, 0.19, 0.38, 0.95 and 1.9 mg single dose levels. Model predictions properly described the time course of 89Zr-adalimumab in control group in both eyes, blood, heart, liver and spleen over 10 days after the IVT of a single dose of 0.19 mg. Median [IQR] PE in both AUC, 0.92 [0.72-0.99] and Cmax, 1.00 [0.84-1.17] further confirmed model accuracy. EIU model predictions accurately described eyes exposure as well as blood, heart, liver and spleen longitudinal profiles in disease group. Simulations suggested 0.38 mg/eye are needed for persistent reductions of TNF-α in the anterior chamber the eye.