Research Project
10138978
Abstract Studies conducted in the late 1990s concluded that poor pharmacokinetics (PK) and toxicity were major causes of costly late-stage failures in drug development. Antibiotic preclinical development candidates must have the right balance of potency, exposure (PK) and therapeutic index (acceptable ratio between efficacious and toxic concentrations). For infectious diseases with complex and sequestered sites of infection, tissue distribution constitutes another critical feature of drug leads. The integration of in vitro and rodent models of absorption, distribution, metabolism and elimination (ADME), and in vitro toxicity assays, has largely reduced attrition in drug discovery and development. The objective of the Pharmacology Core is to assess each of these properties at the hit-to-lead and lead optimization stages carried out by the medicinal chemists to support the five consortium Projects. We propose to leverage a fully integrated analytical platform and state-of-the-art animal facility available at the Regional Biocontainment Lab of the PHRI (Newark, NJ) to assist the assembled team in developing therapeutic countermeasures to high-threat bacterial agents. Core C Leader, Dr Véronique Dartois, has more than 12 years of experience in the pharmacological evaluation of anti-infectives. To support hit-to-lead programs, we propose a battery of in vitro ADME assays and rodent pharmacokinetic studies with the objective of establishing structure activity relationships. The results are integrated in iterative rounds of medicinal chemistry until compounds exhibit desirable pharmacokinetics, potency and toxicity properties, also called leads. For selected projects where the major barrier is penetration of the compounds through the pathogen?s cell wall and intracellular residence time, we have developed intrabacterial PK assays of uptake, efflux and metabolism. For lead optimization programs, we propose metabolite identification assays, dose escalation PK and tolerability in rodents, tissue distribution by conventional mass spectrometry and laser- capture microdissection, and in vitro safety screens, to guide the nomination of preclinical development candidates. We will conduct pharmacokinetic-pharmacodynamic (PK-PD) studies to optimize doses and dosing regimen of preclinical development compounds. Hollow fiber systems will be used to identify PK-PD drivers of efficacy, and determine the concentration range required at the site of infection in order to achieve maximum efficacy. In summary, we will interact with all projects and all cores to deliver services essential to each drug discovery stage. Adequate prioritization and go-no/go decisions based on ADME and toxicology profiling will minimize the risk of PK- and toxicity-related attrition later in the drug discovery process. !
