Abstract
Purpose :
BIX-02565 is a highly potent, nanomolar range RSKi. Ribosomal protein kinases play an integral role in signal transduction by phosphorylation of cellular substrates. Studies have suggested their role as regulators in the necroptosis of retinal ganglion cells. For proof-of-concept testing, computational modeling and simulation tools for ophthalmic indication discovery, drug repositioning, and optimizing the design of novel ocular formulations were applied towards lead nomination of BIX-02565.
Methods :
Over 50 chemical entities available on www.opnme.com (Boehringer Ingelheim, BI) were screened against Rules of Thumb for Ophthalmic Drugs (ROx) and validated protein targets in an ocular context. BIX-02565 displayed ROx compliancy and optimal ocular ADME properties and was selected for formulation-coupled PKPD modeling. Measured parameters of log P, solubility, CACO permeability, plasma protein binding, and hepatic clearance were used to build and validate a GastroPlus® (Simulations Plus, Lancaster, CA) physiologically based PK model of BIX 02565 in a rat. Next, BIX-02565 was placed into a model for the eye, OCAT®, to predict ocular exposure in relevant tissues of rabbits, comparing [total vs. free-drug] to measured in vitro potency against RSK.
Results :
A peak plasma concentration (Cmax) of 2.98 μg/mL was generated by PBPK model, which closely agreed with observed Cmax of 3.0 μg/mL provided in BI’s rat PK study results. Topical ocular solution dosing in OCAT® of a theoretical 0.1%w/v BIX 02565 dose displayed durable eight-hour coverage of posterior segment tissue (i.e. RPE, choroid) in terms of pharmacokinetic profiles stimulated in a rabbit. While total drug concentrations reached over 100 times higher than the required IC50 nanomolar values for RSKi, the theoretical free drug levels were also predicted after adjusting for pigment/melanin and protein binding.
Conclusions :
OCAT® PBPK model suggests that once daily dosing of solubilized eyedrops of BIX-02565 provide total exposures at steady state to afford sufficient target inhibition. By inhibiting RSK activity, BIX-02565 can disrupt signaling pathways in necroptosis, providing a novel approach to rescuing retinal neurons, a possible in vivo proof-of-concept/mechanism study. The ophthalmic repurposing of BIX-02565 serves as a promising therapeutic approach for the treatment of retinal degenerative disorders.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.