Our work

Early human ADME data in drug development

Accurate prediction of absorption, distribution, metabolism and excretion (ADME) and adverse drug reactions (ADRs) is often difficult. At TNO we have developed in vitro and ex vivo platforms. Combined with our microbiome and AMS platforms, these give us a broad portfolio for predicting and measuring early human ADME/DMPK.

Interested in accelerating your drug development?

Contact Steven Erpelinck for more information.

Contact

Preclinical human DMPK

InTESTine, an ex vivo intestinal tissue model

InTESTine™ enables the investigation of the absorption, interaction and translocation of pharmaceutical, biological and nutritional compounds across the intestinal wall. In this physiologically relevant medium-throughput system, fresh ex vivo intestinal mucosal tissue of human or animal origin is mounted into a two-compartment model with an apical and basolateral side.

Drug transporters

TNO offers a broad portfolio of drug transporter assays, including cell-based transporter  assays (bi-directional transporter assays as well as accumulation assays). We provide a broad range of human and rodent transporter assays in CaCo-2, MDCK, and HEK293 cells, including the ones recommended by the FDA/EMA. Additionally, we can perform LCMS/MS based transporter protein quantification.

I-screen, a human gut microbiome screening platform

I-screen can be used to evaluate the effects of substances (e.g. drugs, nutrients) on the human gut microbiota composition and functioning and vice versa: the effects of human gut microbiota on drug metabolism and reductions. I-screen uses physiologically relevant  anaerobic conditions and culture media  to mimic human colon microbiota conditions.

Ex vivo liver

Currently available in vitro liver models often fail to predict PK, mainly due to absence of biliary excretion route. TNO has developed an ex vivo liver platform using whole perfused livers of porcine origin. This platform enables the investigation of:

  • Biliary excretion
  • Hepatic clearance & metabolism
  • Effect of DDIs on plasma kinetics
  • Liver Safety Assessment

Plasma protein binding (PPB)

The binding of drugs to plasma proteins has major consequences for their pharmacokinetic properties. Many methods for determining the free fraction of a drug in blood plasma have been described. There is still an unmet need for a highly sensitive PPB assay for hydrophobic and highly binding drugs. For this class of compounds we have developed a competitive partitioning to a polymer phase assay (ComP3). The results of the ComP3 assay are highly reproducible (assay sensitivity: free fraction in human plasma < 0.05%).

Early clinical ADME data

TNO has access to two accelerated mass spectrometers (AMS) facilitating microdosing & microtracer studies. 14C-labelled drugs are administered to human volunteers or patients, followed by measuring parent drug and/or metabolites in different matrices (blood, plasma, urine, faeces) as early as possible in clinical development using auto-combustion-based AMS.

Microdosing AMS studies (Phase 0)

Used for candidate selection based on PK characteristics after administration of a microdose (<100ug, < 1uCi) to human subjects.

Microtracer AMS studies

A classical Phase 1 study, oral administration of a cold therapeutic dose, can be extended with IV administration of a 14C-labelled microtracer at Tmax, to generate absolute bio-availability (AbsBA) at an early stage of development. Additional microtracer studies will generate mass balance and MIST data, thus accelerating and de-risking clinical development.

Contact

Steven Erpelinck BSc. MBA

  • bioavailability
  • microdosing
  • AMS transporters
  • permeability
  • PBPK modeling
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