Abstract
Purpose :
Progressive computational methods play a crucial role in ophthalmic drug discovery, enabling a more cost-effective and accelerated approach. Boehringer Ingelheim showcases preclinical data on various molecules for public access to meet areas of unmet medical need. A bradykinin 1 receptor antagonist, BI-113823, was found to have ophthalmic potential through literature searches, analysis of in vitro pharmacology druggability criteria through ADMET Predictor®, and GastroPlus® OCAT for ocular PKPD.
Methods :
PubMed literature searches were conducted to determine its potential for ophthalmic therapeutics. BI-113823 SMILES was input into ADMET Predictor®, and "rules of thumb" for topical ophthalmic drugs (ROx) were calculated for optimal corneal permeability. BI-113823 demonstrated adequate solubility and a distribution coefficient value at pH 7.4 affording multiple methods of ocular delivery simulations (e.g. topical and injectable). In vivo and in vitro DMPK/CMC parameters from www.opnme.com were input into GastroPlus® & OCAT to build and validate a physiologically based pharmacokinetic (PBPK) model in mice and rats, and translate it to an ocular PK.
Results :
BI-113823 was found to have potential in diabetic retinopathy and retinal inflammation. The GastroPlus® mouse and rat model simulations resulted in Cmax and AUC0-inf values of within 30-50% confidence intervals of nonclinical reported data. PBPK models could be compared to Boehringer Ingelheim’s openMe database data which showed a Cmax of 3100 and 1230 nM, and an AUC0-inf of 7240 and 2390 nM*h, for mice and rats. Topical and intravitreal ocular dosing simulations in OCAT® of a theoretical BI-113823 formulations (0.01-1mg range) displayed durable coverage of posterior segment tissues (i.e. RPE, choroid) in terms of pharmacokinetic profiles stimulated in a rabbit. Total drug concentrations surpassed hB1R (IC50) of 6.97 nM, and the theoretical free drug levels were also predicted adequate at steady state after adjusting for melanin and protein binding.
Conclusions :
The use of computer aided drug discovery is an innovative method which promises to be a powerful tool in ophthalmic pharmacokinetics and drug delivery predictions within the context of repurposing. BI 113823 displays exceptional repurposing potential for treatment of ocular diseases such as diabetic retinopathy and retinal inflammation.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.