Javier Reig-lopez1,2, Xurxo GarcÃa-Otero3, Marina Cuquerella-Gilabert1,2, Enrique Bandin-Vilar4,5, Anxo Fernandez-Ferreiro4,5, Pablo Aguiar-Fernandez3,6, Victor Mangas-Sanjuan1,2, Francisco Javier Otero-Espinar7, Virginia Merino-Sanjuan1,2, Matilde Merino-Sanjuan1,2
1Departamento de Farmacia y TecnologÃa Farmacéutica y ParasitologÃa, Universitat de València, 2Instituto Interuniversitario de Investigación de Reconocimiento Molecular y Desarrollo Tecnológico (IDM), Universitat de València-Universitat Politècnica de València, 3Molecular Imaging and Pharmacokinetic Modelling Group, CIMUS, University of Santiago de Compostela, 4FarmaCHUSLab Group, University Clinical Hospital, Health Research Institute of Santiago de Compostela (IDIS), 5Pharmacy Department, University Clinical Hospital, Santiago de Compostela (SERGAS), 6Nuclear Medicine and Molecular Imaging Group, University Clinical Hospital, Health Research Institute of Santiago de Compostela (IDIS), 7Paraquasil Group, Institute of Materials (iMATUS) and Health Research Institute of Santiago de Compostela (IDIS)
Introduction. As the incidence and prevalence of eye diseases is expected to increase, the optimisation of dosing strategies and the development of drug delivery systems becomes a critical necessity. Objectives. The aim of the present work was to develop a physiologically based pharmacokinetic (PBPK) model of 89Zr-adalimumab after intravitreal (IVT) administration in healhty and endotoxin-induced uveitis (EIU) diseased rats to assess the effect of dose on TNF-a reduction in the anterior chamber of the eye. Methods. A full PBPK model was created in PK-Sim® and exported to MoBi®, where the eye tissue was created following the structure previously reported by Bussing and Shah [1]. Cervical lymph nodes were also included and linked to both eyes through the lymphatic system. The model considered the two-pore formalism [2] as well as neonatal Fc receptor (FcRn) binding in endosomes and competitive processes with endogenous IgG. Moreover, a soluble binding partner (TNF-a) in plasma and interstitial spaces was also included. A temporal increase in posterior-to-anterior cavities flow (Qva) and in aqueous humour drainage (Qah) because of the reversible increase in intraocular pressure after IVT administration was implemented. In order to properly track the radioactivity in blood (total activity) and tissues (ß-decay), the natural decay of 89Zr was considered for the drug (native and degradation products) and complexes (FcRn and TNF-a). Additionally, residual radioactivity coming from 89Zr-adalimumab lysosomal degradation was also quantified. Disease model incorporated pathophysiological changes related to anterior uveitis such as breakdown of blood-aqueous barrier, increased TNF-a synthesis and ocular hypotony [3]. Anatomical and physiological parameter values for systemic compartments were kept as reported by PK-Sim® and those related to eyes were allometrically scaled down from rabbits [1]. Simulations consisted in the IVT administration of 0.19 mg of 89Zr-adalimumab (1.74 MBq/eye) through a single injection of 4 uL in both eyes. Model evaluation consisted in graphical comparison of predicted vs observed (radioactivity) in blood, eyes, cervical lymph nodes, heart, liver and spleen as well as a numerical assessment determining AUC and Cmax prediction errors (PE). The PBPK model was ultimately used to assess the effect of IVT administered adalimumab on TNF-a reduction in aqueous humour and ICB of EIU rats over a single ascending dose (SAD) design. The dose levels evaluated were 0.019, 0.038, 0.095, 0.19, 0.38, 0.95 and 1.9 mg. Deterministic simulations over 60 days were performed. Results. Model predictions properly described the time course of 89Zr-adalimumab in control group (n=3) in both eyes, blood, heart and spleen over 10 days after the IVT of a single dose. Liver exposure was slightly overpredicted most probably because of the difference between its volume (10 mL) and the region of interest used in the experimental procedure (0.343 mL). Median [IQR] PE in both AUC, 0.92 [0.72-1.25] and Cmax, 1.00 [0.84-1.49] further confirmed model accuracy. EIU-related pathophysiological changes resulted in a blood-aqueous humour reflection coefficient reduced from 0.95 to 0.1, a 7-fold faster TNF-a synthesis and a 5-fold reduction in Qva and Qah, which is in line with previous reports evaluating ocular inflammation [4,5,6]. EIU model predictions accurately described eyes exposure as well as blood, heart and spleen longitudinal profiles in disease group (n=6), again with an overprediction in liver. PE in both, AUC and Cmax fell within 0.5-2 except for liver (7.29 and 6.92, respectively) and cervical lymph nodes (2.60 and 4.5, respectively). SAD simulations suggested TNF-a reduction in aqueous humour and ICB interstitial fluid is as high as 76% at lowest dose (i.e., 0.019 mg), while changes below baseline concentration in plasma would only be achieved above 0.38 mg. Regarding to target recovery, 0.95 mg are needed to keep TNF-a levels below baseline over 2 and 6 days in plasma and interstitial fluid of ICB, respectively. Conclusions. The PBPK model here reported represents a consistent basis to mechanistically explore radiolabeled biologic drugs disposition after IVT administration and allows to perform translational modelling between species and dose schedule optimisation. The incorporation of radioactivity-related processes allows the use of observed data coming from non-invasive (images) preclinical experiments.
[1] Bussing D, Shah DK. Development of a physiologically-based model for ocular disposition of monoclonal antibodies in rabbits. J Pharmacokinet Pharmacodyn. 2020; 47:597-612. [2] B. Rippe and B. Haraldsson. Transport of macromolecules across microvascular walls: the two-pore theory. Physiol Rev. 1994 Jan;74(1):163-219. [3] Cuartero-Martínez A. et al. Preclinical characterization of endotoxin-induced uveitis models using OCT, PET/CT and proteomics. Int J Pharmaceutics. 2024; 662:124516. [4] S. Schwager, M Detmar. Inflammation and Lymphatic Function. Front Immunol. 2019; 10(308). [5] Alex F. de Vos et al. Kinetics of Intraocular Tumor Necrosis Factor and Interleukin-6 in Endotoxin-Induced Uveitis in the Rat. Invest Opht Visual Sci. 1994; 35(3). [6] X. Garcia-Otero et al. Anti-Inflammatory Effect of Tacrolimus/Hydroxypropyl-?-Cyclodextrin Eye Drops in an Endotoxin-Induced Uveitis Model. Pharmaceutics, 2021, 13(10), 1737.
Reference: PAGE 33 (2025) Abstr 11643 [www.page-meeting.org/?abstract=11643]
Poster: Drug/Disease Modelling - Absorption & PBPK