ADME-Tox
The Reaction Oncology Platform

ADME-Tox

The integrated approach of the Reaction Oncology Platform provides testing of ADME-tox parameters (Adsorption, Distribution, Metabolism, Excretion, and Toxicity) throughout the whole drug discovery process.

Reaction Biology offers a basic suite of ADME assays in-house, such as:

  • CYP enzyme inhibition assays
  • In vivo PK/PD studies in mice
  • Plasma Inhibitory Assay to define the impact of plasma proteins on the function of new drug candidates
  • Safety panel to test off-target effects on a selection of 40 GPCR, ion channels, transporters, and enzymes whose inhibition may cause toxic side effects.

To provide our clients a complete portfolio of ADME-tox services, we work with a team of specialists from the high-quality ADME-tox provider Admescope. Partnering with an experienced ADME-tox CRO ensures the creation of drug candidates with a favorable pharmacologic profile necessary for approval by regulatory bodies. Admescope is a part of our medicinal chemistry partner Symeres, aiding well-tuned communication routines and logistics for short cycle times to realize optimal drug discovery.

With the integrated ADME-Tox capabilities, we support the project in the hit-to-lead, lead optimization, and preclinical development phase. The tailorable services are widely spread over the whole nonclinical ADME-Tox area: in vitro & in vivo drug metabolism; including metabolite profiling & identification, drug-drug interactions, pharmacokinetics on different rodent species, and quantitative bioanalysis.

With an eye on the regulatory requirements for successful IND application, we integrate ADME readouts into the drug discovery process to ensure:

  1. To only advance drugs with a favorable pharmacological profile.
  2. Hone the drug candidates early in the process to ensure high bioavailability in the organism.
  3. Determine drug-drug interactions, in vitro toxicity, and inhibition of metabolic enzymes to ensure low side effects.

In vitro safety panel screening - Early identification of off-target toxicity

For early identification of potential side effects due to off-target interaction, Reaction Biology tests new drug candidates with a panel composed of GPCRs, transporters, kinases, drug-metabolizing enzymes, and ion channels. Drug interactions with these targets have been shown to result in undesirable side effects of treatments in patients.

Detecting off-target interactions early in the drug discovery process enables medicinal chemists to optimize structure-activity relationships to help ensure that potentially valuable drug candidates will not fail during preclinical in vivo toxicology or phase I testing.

Our ability to perform functional assays with many of the panel targets allows for fast follow-up testing of positive activities in the primary binding assays.

The effects of plasma proteins on a drug's performance.

Question

The Plasma Inhibitory Assay is a tool for measuring the efficacy of inhibitors in the presence of plasma protein

Challenge

One factor determining the bioavailability is the impact of plasma proteins binding to a drug, potentially rendering it ineffective. We needed to measure the plasma inhibitory activity (PIA) on FLT3 inhibitors for a drug discovery study.

Achievement

We have employed our FLT3 Cellular Phosphorylation Assays to determine the efficacy of two FLT3 inhibitors, Sorafenib and Sunitinib, in the presence and absence of plasma proteins. In an in vitro study, we incubated the inhibitors with either a plasma-free medium or a plasma-containing medium before subjecting them to the cellular phosphorylation assay with the readout of FLT3 autophosphorylation via ELISA.  The reference inhibitors are examples of inhibitors being susceptible (Sorafenib) and unsusceptible (Sunitinib) to plasma binding.

The determination of bioavailability in mice is performed similarly: At different time points after drug administration blood samples are taken and the effective compound concentration will be measured via the Cellular Phosphorylation Assay. The PIA assay is used in clinical trials as a surrogate for pharmacodynamic analysis of FLT3 inhibitors in patients.

PIA

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Determination of the Plasma Inhibitory Activity on Drugs based on the Cellular Phosphorylation Assay.