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ADME/DMPK

Early characterization of in vitro absorption, distribution, metabolism and excretion (ADME) and in vivo pharmacokinetic (PK) properties have become an integral part of modern drug discovery, critical for the selection, progression and development of new drug candidates.

Selvita offers a comprehensive selection of well-established in vitro ADME assays, designed to characterize physicochemical properties of compounds, as well as metabolism, binding, permeability and drug-drug interactions.  This expertise is used to further optimize, rank and de-risk compounds and, together with additional in vitro biologically relevant readouts (potency, selectivity, safety), to select compounds for in vivo pharmacokinetic, target engagement (TE) and pharmacodynamic (PD) studies.  Throughout this process, in vitro-in vivo extrapolations are validated and early PK data is simulated to guide early projections to man.  Our bioanalytical capabilities support a range of analytical techniques, most often through quantitative and qualitative analyses based on liquid chromatography and tandem mass spectrometry.  A team of skilled bioanalytical scientists are experienced in biomarker assays in addition to developing methods designed to support various in vivo studies (PK, PD, Tox).

Selvita’s accomplished ADME/PK experts are engaged in designing tailored screening cascades as well as in vitro and in vivo studies, to enable the understanding of specific challenges and facilitate the progression of a project in an appropriate and timely manner.  Compounds are often screened in a range of in vitro ADME and in vivo PK set-ups using a tiered approach, which can be modified to suite the client’s requirements.  Such studies are offered either as stand-alone projects or as a part of a collaborative Integrated Drug Discovery (IDD) program.  Complemented with cost-efficient, high throughput technologies and streamlined processes, we ensure high quality data and rapid turnaround time aimed at reducing the time from request to result.  Selivta’s DMPK scientists work toward interpreting and understanding data within project teams and have scientific expertise to provide guidance and consultancy services to our Clients.

DMPK services

ADME platform

  • Physico-Chemical Profiling
    • Kinetic Solubility- Thermodynamic Solubility
    • Lipophilicity (LogD, LogP), pKa
    • Chemical Stability
  • In vitro permeability and transporters
    • PAMPA
    • Cellular permeability (Caco-2, MDCK, MDCK-MDR1)
    • P-gp substrate identification
  • In vitro metabolism and drug-drug interactions
    • Metabolic stability (microsomes, S9, hepatocytes, plasma, blood)
    • Aldehyde Oxidase reaction phenotyping
    • Cytochrome P450 inhibition and metabolism-dependent inhibition
    • Metabolite Profiling and Identification using high-resolution mass spectrometry
    • Reactive metabolite screening
  • Protein binding
    • Plasma protein binding
    • Tissue binding
    • Blood cell association

Bioanalysis

Our bioanalytical laboratories support a range of services from early discovery to clinic stage projects, using state-of-the-art liquid chromatography-mass spectrometry platforms (LC-MS/MS, LC-MS, LC/HRMS, LC-UV FD).

In a discovery setting, small molecules and peptides are analyzed in a non-regulatory setting via quantitative analysis to measure concentrations of parent and metabolite across various biological matrices, obtained during PK/PD and TK studies. LC and MS methods are optimized to ensure high quality, while minimizing time and cost and are accepted based on pre-defined acceptance criteria.  For later stage projects in preclinical to clinical stages of development, bioanalytical method validations can be performed for small molecules according to EMA/FDA guidelines and in compliance with GLP or GCP regulations.

Bioanalytical services

  • Discovery (non-GLP) bioanlaysis
  • Metabolite profiling and identification
  • Dose-formulation analysis
  • Regulated bioanalytical method development and validation
  • Method development and transfer
  • Cross-validation of bioanalytical methods
  • Analysis of biomarkers

Pharmacokinetics

Our in vivo PK studies are conducted as stand-alone services or within integrated drug discovery projects, in our AAALAC-accredited animal facility and in-line with the highest animal welfare standards, national and EU regulations.  The complexity of studies varies depending on the stage of discovery and can be done using standardized protocols or customized layouts.  PK data is analyzed using Phoenix® WinNonlin® software and can be modelled and simulated to establish PK/PD relationships and in support of pharmacodynamic or safety studies.

PK study designs include:

  • Cassette and single compound rapid PK screening studies in rodents
  • Studies to assess the disposition kinetics and bioavailability in rodetns
  • Dose proportionality (ascending dose)
  • Dose linearity (multiple dose)
  • Excretion studies
  • Tissue distribution studies (non-radioactive)
  • Customized studies (CSF sampling, intestinal loops, knock-out animals)

Various routes of administration (intravenous (bolus and infusion), oral, intraperitoneal, subcutaneous, intramuscular, intranasal, intratracheal, intra-colonic), different sampling routes and a variety of matrices available ensure a broad platform to characterize compounds in vivo.