Retinal physiologically based pharmacokinetic modeling of intravitreally administered large molecules across species

This dissertation focuses on improving our understanding of large molecule ocular pharmacokinetics (PK) in different species and bridging the gap between animal models and human studies. The study utilizes physiologically based pharmacokinetic (PBPK) modeling and mechanistic PK modeling to explore whole-body, as well as ocular PK across the three species rabbit, non-human primate, and human. Initially, this work investigates the translatability of parameters related to neonatal fragment crystallizable receptor (FcRn) binding and target-mediated drug disposition (TMDD) for the therapeutic protein efalizumab. PBPK models were developed for rabbit, non-human primate (NHP), and human, and the parameters were compared between species. The results indicate that while FcRn affinity parameters cannot be translated, parameters related to TMDD can be translated from NHP to human. Furthermore, the dissertation focuses on the simulation of retinal drug concentrations after intravitreal administration in rabbits, aiming to improve our understanding of ocular physiology and drug distribution in the eye. A mechanistic ocular model was developed for bevacizumab. The model successfully describes the concentration-time profiles in the injected eye, plasma, and fellow eye. It also provides insights into the interpretation of retinal volume and permeability, enabling more accurate predictions of drug exposure in the fellow eye. Finally, this work explores ocular PK across rabbits, monkeys, and humans, emphasizing the importance of cross-species translation in ocular pharmacokinetic studies. Extended mechanistic ocular models were developed for each species using ranibizumab in a case study. The models successfully describe the PK data in all three species and highlighted inter-species differences in vitreous-to-aqueous diffusion rates and systemic drug disposition. Overall, this dissertation contributes to the improvement of ocular PK modeling across different species and provides valuable insights into the translation of large molecule models. The findings enhance our understanding of general cross-species PK, as well as ocular drug PK and support the development of more accurate predictions for human dose estimation and ocular drug exposure.