In silico simulation models for preclinical pharmacokinetic profiling in drug repositioning of a cathepsin S inhibitor for age-related dry eye

Abstract

Purpose : Novel in silico models may be used as an alternative to animal models for preclinical pharmacokinetic-pharmacodynamic (PKPD) profiling. We employ a simulation software suite (Simulations Plus Inc., Lancaster CA) to define the boundaries of ocular pharmacokinetics and drug delivery and characterize drug candidates. This can serve as a basis for preclinical proof-of -concept/-mechanism studies of BI-1124, a repositioned asset in ophthalmic indications for dry eye diseases.

Methods : Repositioning potential of available compounds on www.opnme.com (Boehringer Ingelheim, BI) was scored through an ocular target literature search and analysis with ADMET Predictor® for "rules of thumb" for topical ophthalmic drugs (RO_x). Simulated testing with GastroPlus® OCAT module showed the accuracy of these in silico models by comparing BI in vivo oral dosing data to the in silico data, and, upon p.o. PBPK model validation, an ocular simulation was linked and translated for pre-clinical exposure of BI-1124.

Results : Of 58 molecules, 5 had high corneal permeability while maintaining adequate solubility and distribution coefficient at pH 7.4. BI-1124 was determined to have repositioning potential for age-related dry eye indications through mechanistic inhibition of cathepsin S. The simulated C_max of an IR solution of BI-1124 in a mouse closely matched manufacturer’s C_max of 0.152µg/mL (370nM). Translating and connecting to OCAT® model for a theoretical topical ophthalmic solution of BI-1124, simulations in rabbits displayed adequate PKPD coverage, as total [BI-1124] reached and maintained in vitro IC₅₀ of 7nM=0.00285µg/mL, at a dose of 0.075mg/ml. Times until bioavailable concentrations fell below IC₅₀ in cornea and conjunctiva at 0.0075%w/v were 7.067 hours and 5.2 hours, respectively. The concentration required for IC₉₉ was predicted to be 70nM=0.0285µg/ml, and at same dose provided 4.32 hours and 2.4 hour corneal and conjunctival coverages, respectively.

Conclusions : Validating PBPK models with available in vivo experimental data before investigating ophthalmic repositioning ensures that in silico models are accurate and reliable. In vitro DMPK and CMC parameters and in vivo DMPK and pharmacology data strengthen the models’ credibility. The simulated duration of IC₉₉ levels indicates a promising ophthalmic coverage for BI-1124, justifying future preclinical research.

This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.