(W-039) Predictive Pharmacokinetic Analysis of Novel PLCG2 Inhibitors Using GastroPlus and ADMET Predictor

Brent Clayton, Phd – Associate Research Professor of Medicine, Indiana University School of Medicine; Lais Da Silva, Phd – Research Assistant Professor, Indiana University School of Medicine; Sara Quinney, Phd – Professor, Indiana University School of Medicine; Timothy Richardson, Phd – Senior Research Professor of Medicine, Indiana University School of Medicine

Objectives: : Over the last twenty years, there has been a growing utilization of different in vitro models within the pharmaceutical sector to examine absorption, distribution, metabolism, and excretion (ADME) processes. This surge can be attributed to the significant role that poor ADME properties play, accounting for 40% of drug candidate setbacks during the clinical phase of drug development]In the quest to develop effective treatments for Alzheimer's Disease (AD), a series of novel compounds targeting PLCG2 were evaluated using in silico physiologically based pharmacokinetic (PBPK) modeling

Methods: Utilizing GastroPlus and ADMET Predictor, we simulated the pharmacokinetic profiles of eight compounds. The aim was to predict oral bioavailability, plasma and brain exposure, and other critical pharmacokinetic parameters following a 0.25 mg dose administered as an immediate-release (IR) solution.



Results :The compounds exhibited high absorption, with the fraction absorbed (Fa) and the fraction of dose permeated (FDp) nearing 100% for all compounds. The fraction of the dose that reaches systemic circulation (F) ranged from 60.649% to 79.631%. Peak plasma concentrations (Cmax) varied between 7.5914 µM and 20.887 µM, with time to reach peak plasma concentration (Tmax) occurring at 0.16 to 0.24 hours. The highest brain concentrations (Cmax Brain) were observed with TAD-0411074 and TAD-0411110, at 54.598 µM and 75.465 µM, respectively. Area under the curve (AUC) from zero to infinity (AUC0-inf) and to the last measured time point (AUC0-t) highlighted the systemic exposure, with TAD-0411110 achieving the highest AUC0-inf at 50.365 µg·h/mL. Liver exposure (Cmax Liver) and unbound plasma (CmaxU plasma) and brain (CmaxU Brain) concentrations provided insights into the distribution and potential efficacy within target tissues. The compounds demonstrated varied half-lives, ranging from 1.12 hours for TAD-0411797 to 8.71 hours for TAD-0410462.



Conclusions: These findings underscore the potential of these PLCG2 inhibitors as promising candidates for AD treatment, meriting further in vivo investigation and optimization.

Citations: 1. Cai, H., et al., Evaluation of an integrated in vitro–in silico PBPK (physiologically based pharmacokinetic) model to provide estimates of human bioavailability. International journal of pharmaceutics, 2006. 308(1-2): p. 133-139.