Pharmacokinetics and Drug Metabolism

National Center For Advancing Translational Sciences

Investigators

Linked publications & trials

Abstract

The DMPK group has supported diverse projects across DPI, contributing significantly to all stages of translational research at NCATS, from early probe development in drug discovery to Phase II clinical trials. Our major capabilities include: 1. In vitro ADME high-throughput screening (Tier I HTS assays) on solubility, permeability and microsomal stability for all small molecule compounds registered at NCATS (3000 compounds/year). 2. Customized in vitro ADME assays (Tier II assays) as required by each projects specific needs. The common Tier II assays include metabolic stability in different species, metabolite identification (MetID), aldehyde oxidase stability in cytosol fraction, plasma stability for prodrugs and biologics, blood/plasma partition, CYP inhibition, and transporter assessments in Caco-2 and MDKC cells. 3. PK studies in lab animals and bioanalytical measurements of drug concentrations in different biological fluids (e.g., blood, plasma, urine, bile) and tissue extracts. 4. UPLC-MS/MS and high-resolution accurate mass spectrometry for quantitation of small molecules and peptides, and structure identification of metabolites. 5. Bioanalytical method development for therapeutic macromolecules, such as recombinant human proteins and engineered proteins. 6. Pharmacokinetic parameter calculation and simulation. Scientific data generated from our lab have been used for novel target validations, IND filing or clinical trials and research publications. Examples of the DMPK group contributions to recent projects within the Therapeutic Development Branch include: Rapid Response to COVID-19 Pandemic: When the COVID-19 outbreak occurred in early 2020, our lab responded quickly to this public health crisis. We have worked on several drug discovery and development projects related to COVID-19 treatment: 1. Repurposing emetine: Pharmacokinetics and tissue concentrations were determined in relevant animal species for efficacy assessment. Our data were used to guide dose selection in the efficacy study. 2. In vitro ADME and in vivo PK studies on a novel niclosamide prodrug: In vitro biology data have suggested that niclosamide is active against SARS-CoV-2. However, oral absorption of niclosamide is very poor. To improve oral bioavailability, a prodrug approach is being applied to increase oral absorption. Pharmacokinetics and tissue concentrations of the prodrug were determined in relevant species. These data will be used to support the in vivo proof-of-concept efficacy study in animal models of disease. 3. Development of GS-441524: To support development of an orally available anti-viral drug (GS-441524, a metabolite of Remdesivir), we conducted a series of in vitro ADME and in vivo PK studies in different species. These data helped NCATS scientists determine to advance this molecule to IND-enabling studies. Our data are available to the public via the NCATS OpenData Portal (https://opendata.ncats.nih.gov/covid19/GS-441524). In Silico ADME Modeling: Characterization of in vitro ADME properties of a novel compound is very important in drug discovery research as it will guide structure optimization and lead selection. We have developed high-throughput assays for key ADME properties, such as aqueous solubility, membrane permeability and hepatic metabolic stability in microsomes. To date, we have collected data for approximately 20,000 compounds synthesized or registered at DPI/NCATS. To ensure data quality, we use controls in each plate and monitor performance for all plates. We calculate Minimum Significant Ratio (MSR) for controls, a statistical parameter that characterizes the reproducibility of an assay, in order to evaluate assay performance. With high quality datasets in hand, we start to develop in silico models for these ADME properties. These in silico models are useful tools for medicinal chemists to design new drug-like molecules, which will potentially reduce the number of compounds to be synthesized during drug discovery, save valuable resources, minimize chemical waste, and ultimately help to accelerate the drug discovery process. The assay protocols for ADME Tier I and Tier II assays have been published in PubChem (as of August 1, 2021), and the corresponding in silico models can be found at NCATS OpenData Portal: Kinetic Aqueous Solubility; PubChem BioAssay AID: 1645848; https://opendata.ncats.nih.gov/adme/models/solubility PAMPA Permeability (pH 7.4); PubChem BioAssay AID: 1508612; https://opendata.ncats.nih.gov/adme/models/pampa PAMPA Permeability (pH 5); PubChem BioAssay AID: 1645871; https://opendata.ncats.nih.gov/adme/models/pampa Tier I Rat Liver Microsome Stability; PubChem BioAssay AID: 1508591; https://opendata.ncats.nih.gov/adme/models/rlm Mouse Cytosol Stability; PubChem BioAassay AID: 1508604 Human Cytosol Stability; PubChem BioAssay AID: 1508603