ABSTRACT - Pharm Core 5 To be tested in efficacy studies and advance to preclinical development, small molecule antivirals must have the right balance of potency, exposure (pharmacokinetics, PK), and therapeutic index (acceptable ratio between efficacious and toxic concentrations). The Pharmacology Core will support advancement of promising hits and leads through tiered absorption, distribution, metabolism, and elimination (ADME) assessment and harmonized gating criteria, selecting compounds and chemical scaffolds with the essential attributes for efficacy studies and preclinical development. The Core will leverage a fully integrated analytical platform and state-of-the-art animal facility available at the Center for Discovery and Innovation, Hackensack Meridian Health (Nutley, NJ) to assist the assembled team. The Core Leader, Dr Véronique Dartois, has extensive experience in the pharmacological evaluation of anti-infective compounds, including 8 years supporting anti-Dengue drug discovery programs in the pharmaceutical industry. To support hit-to-lead programs, we will carry out physicochemical and in vitro PK profiling as well as basic formulation development and in vivo snapshot PK in mice via different routes of administration. The data will be used to establish structure-activity relationships, to nominate leads and guide compound progression towards efficacy evaluation, according to conventional phase transition criteria. To support lead optimization programs, we will perform safety screens, full mouse and hamster PK, tissue distribution in pulmonary fluid and nasal compartments, intracellular uptake, and prodrug conversion studies. In close collaboration with all Projects and the Animal Model Core, we will integrate (i) plasma and pulmonary PK, (ii) plasma protein binding, (iii) uptake in relevant cell lines to factor in active transport/efflux processes, and (iv) potency measurements, to calculate pharmacokinetic-pharmacodynamic indices in plasma and at the site of infection, and to propose doses for tolerability and efficacy studies. Plasma and tissue concentrations will be monitored during murine and hamster efficacy studies. Harmonized threshold metrics will guide lead optimization and go-no/go decisions to minimize the risk of PK- and toxicity-related attrition later in the drug development process.