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Pharmacokinetics, Dynamics & Metabolism (PDM)

pharmacokinetics-pharmacodynamics-and-metabolism

PDM is focused on the development of innovative small and large molecule therapies through an improved understanding of targets, pathways and modeling for preclinical efficacy, discrete toxicity, and safety biomarkers. PDM will pursue collaborations to enhance biomarkers/biomeasures, systems pharmacology/PKPD, quantitative bioanalytics, prediction of transporter-mediated disposition, tissue targeting capabilities, oral delivery of peptides, and mitigation of immunogenicity risk.

WRD is interested in establishing alliances to develop and access:

  • Translational research — large and small molecule efforts
    • Systems Pharmacology / PKPD / Quantitative Biomeasures: deeper knowledge of targets and pathways; increased confidence in target selection; increased confidence in drug selection
    • Systems models of discrete areas of toxicity, e.g., cardiovascular toxicity
    • Application of PKPD to safety biomarker technologies
    • Influence of hepatic and renal uptake and clearance on toxicology in these organs — focus on disorders of bile production and bile acid transport
  • Quantitative Bioanalytics, Biomarkers, Biomeasures, and Immunogenicity (ADA) Assays — large and small molecule efforts
    • Novel LC/MS large molecule bioanalysis and automation techniques (e.g., nano LC, SISCAPA, advanced immunocapture techniques, tissue analysis)
    • FACS-based cellular imaging techniques for biomarkers and biomeasures
    • Biosimilars / Biocomparability
    • Key vendor development for biotherapeutics bioanalytical capabilities in (a) various platforms (e.g., mass spectrometry-based, ligand-binding assays, flow cytometry) across various modalities, (b) quantitative biomarker capabilities in support of biomarker / biomeasure studies, and (c) regulated toxicology and clinical sample analyses
    • Next-generation of advanced intelligent high-throughput automation platforms for bioanalysis
    • Novel / emerging chromatographic separation techniques (high throughput, high resolution, green chemistry)
  • Disposition of Antibody-Drug Conjugates — large and small molecule efforts
    • Cellular and systemic fate of the conjugate and components
    • Quantification and prediction of pharmacokinetics
  • Disposition and oral delivery of peptides — large and small molecule efforts
    • Novel commercially viable delivery technologies (oral and non-oral)
    • Predictive tools and technologies targeting oral absorption and disposition of peptides
  • Targeting, prediction and modeling of transporter-mediated disposition and DDIs — small molecules
    • Specific tissue targeting
    • Quantitation and scaling of transporters for input into physiological PK models of tissue penetration and clearance
    • Determination of intracellular unbound concentrations of transported drugs
    • Prediction and quantification of human transport mediated (e.g. biliary) clearance
    • Influence on renal and hepatic toxicology
  • Immunogenicity prediction (in conjunction with efforts in PDM Translational Research and Drug Safety R&D) — large molecules
    • In silico immune epitope prediction
    • In vitro drug-specific immune response (e.g., PBL stimulation; whole protein & epitope mapping; DC-T cell assays)
    • Ex vivo immune response biomarkers (e.g., clinical sample analysis capability; cytokine profiles; innate immune system activation markers; drug-specific subpopulations; pre-existing antibodies)
    • Nonclinical models for predicting immunogenicity impact of product-related risk factors
    • Technologies that mitigate immunogenicity risk (e.g., deimmunization, Tregitopes, formulations, masking conjugates)
  • Physiologically relevant in vitro assays
    • Methods for expanding cell numbers or stabilizing phenotypes of directly isolated primary cells (particularly from patients)
    • Robust, reliable in vitro differentiation protocols from human pluripotent stem cells for difficult to obtain cell types (e.g. brown adipose, kidney podocytes, specific neuronal subtypes, lung epithelial cells, etc.)
    • Novel methodologies for efficient, targeted genetic modification of primary and stem cells
    • Novel, medium to high throughput in vitro assays that translate to activity in the clinic using cell lines that express endogenous levels of target of interest in human primary cells and stem cells
    • Assay technologies that minimize cell use or efficiently discriminate responding cells from a population of heterogeneous cell types
    • Non-natural amino acid substitutions in target proteins to create novel screening readouts (e.g. DFG out for kinases)
    • Genetically encoding phosphorylated amino acids into specific positions
    • Advances in human genome editing technologies for High Content Analysis cell based assays
    • Biosensors and endogenous gene reporter models in human primary cells and stem cells
    • Detection of tagged-protein at physiological relevant concentration in human cell based assays (targeted reporter gene)
    • Visualization of drug interaction with targeted-protein within the cellular environment
    • Quantification of cellular environment changes by biosensors
    • Advances in high content analysis in 3D culture system
  • In vitro Phenotypic Screening:
    • Novel deconvolution advances for in vitro phenotypic screening
    • Prediction of in vitro cellular phenotypic changes due to patient-derived single point mutation and genetic defects
    • Quantification of electro-physiologic measurement in plate cell based assays
  • Advances in single cell mass cytometry technology for phenotypic screening

R & D Brochure

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Understand what R&D is looking for in an early stage opportunity.

 

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