ADME/FORMULATION Core

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SUMMARY The ADMET/Formulation Core (Core C) provides ADME, formulation, pharmacokinetics, and toxicology information to inform project teams for optimizing hits and leads from screening campaigns all the way through good laboratory practice (GLP) and into investigational new drug (IND) status for further testing in humans. This core is centered within Calibr in the CAMPP consortium and will interface closely with investigators within Scripps and other institutions who have complementary capabilities in drug discovery assays to provide standardized and comprehensive drug profiling services. All programs within the medicinal chemistry core spectrum from formal hit assessment to late lead optimization and preclinical candidate characterization will have ADME/Formulation/PK work conducted in this core. Determination of drug-like properties of the CAMPP projects in the lead optimization and hit to lead stages is essential for optimization of early hits to drug candidates. The ADME/Capabilities include in vitro absorption, distribution, metabolism, elimination (ADME) profiling (cell permeability, plasma protein binding, hepatic microsomal stability, drug-drug interaction assay and in vivo pharmacokinetics in rodents and non-rodents, formulation development, in vitro safety pharmacology, and non- GLP toxicology. In vitro safety assays including cardiotoxicity and mutagenicity will be employed. In vitro ADME assays are important and will be geared toward higher throughput assays for in vitro assessment for SAR purposed (Tier 1 ADME) followed by more complex assay for later stage profiling, like mutagenicity assays including Ames and micronucleus testing (Tier 2 ADME). This core will be thoroughly integrated with Core D to determine drug exposure pharmacokinetic/pharmacodynamic (PK/PD) relationship of compounds and formulation assessment of compounds coming from Med Chem Core B. Finally, this core will be able to prepare an IND for a drug candidate given the extensive experience in filing small molecule INDs that require GLP toxicology studies in rodents and non-rodents through external lab auditing by FDA and on-site visits by Calibr staff. The data generated by this core using drug development assays and pharmacokinetic data will be made available to project teams in real-time along with raw data on assays and mass spectroscopy methods. There is >50 years of collective drug discovery pharmacology and toxicology experience under the direction of Dr. Sean Joseph. This includes facilities with four triple quadrupole mass spectrometers for the intensive bioanalysis capabilities needed to support multiple parallel chemistry programs.