Pharmacology/Mycology Core

Johns Hopkins University, Baltimore MD

Investigators

Abstract

SUMMARY The escalating threat of drug-resistant invasive fungal infections underscores the urgent demand for novel therapeutic and diagnostic interventions. The CETR Pharmacology and Mycology (Pharm/Myco) Dual Core was established to provide comprehensive in vitro and in vivo assessments of antifungal efficacy and pharmacologic suitability of novel compounds undergoing advanced lead optimization for selection of preclinical development candidates (PDCs) and entry into IND enabling and de-risking studies. The Core provides timely assessments of key drug attributes including pharmacokinetics (PK), pharmacodynamics (PD), absorption, distribution, metabolism, and excretion (ADME), tiered toxicology, other key parameters, as well as microbiologic support to facilitate metric-based ‘go, no-go’ assessments of compounds for PDC selection and IND-enabling studies. The Pharm/Myco Core functions as an integrated component of the overall drug accelerator, which involves close interactions with all Projects and Cores. The Pharmacology Team offers comprehensive support for in vitro and in vivo PK/PD profiling, ADME, microsomal stability, in vitro physicochemical and drug metabolism, DMPK, and expanded PK analysis. The Team also conducts in vitro, ex vivo and in vivo assessments of safety, intracellular uptake, and drug distribution in infected tissues and fluids. A critical function of the Core is support for advanced pre-IND and IND-enabling studies of PDCs, which is managed through Contract Research Organizations (CROs) for advanced ADME studies, PK-PD assessments, and tiered toxicological profiling. The Core supports GLP and toxicology studies focusing on mitigating toxicological risks and determining drug target achievement for human dose projections, with support from expert consultants in pharmacodynamic modeling and toxicology. The Mycology Team component will determine in vitro antifungal properties of compounds through standardized antifungal susceptibility assays and assessments of drug resistance. They will support microbial burden evaluations in tissue, blood, and urine specimens from animal models. The Core contains 2000+ fully characterized (MIC, genetic, MOA) clinical isolates of drug susceptible and resistant fungi for use by projects, and they will be the liaison with external CROs for expanded evaluations. The Core will also facilitate clinical specimen collection to support a new diagnostic platform. The Pharm/Myco Core is a mature operation that benefits from an established infrastructure supporting several recent CETR drug accelerator programs. In summary, the Pharm/Myco Core assumes a crucial role in evaluating compounds for advanced lead optimization, PDC selection, and IND enabling and de-risking studies. It focuses on meeting specific Target Product Profile criteria that strike a balance between antifungal potency, compound exposure, and therapeutic index, supporting multiple applications for both an IND and a 510(k) diagnostic.