Metabolities in Safety Testing

MetaSafe helps you to confirm that the exposure to human metabolites is adequate in pre-clinical safety species or to effectively identify potential MIST issues in time through a battery of different types of studies:

  • In vitro cross species comparison (cold or hot) – the first step to evaluate choice of toxicological species.
  • Exploratory in vivo metabolism comparison (cold or hot) – a way to understand the probability of a MIST issue
  • Exposure comparison at steady state between pre-clinical species and man – the ultimate study to evaluate if human metabolites are toxicologically qualified
  • Human radiolabelled ADME metabolite profiling and identification study – the optimal study to define what human metabolites fall under the criteria of FDA and ICH guidelines.

After administration, a drug is usually converted in the liver, GI-tract and/or extrahepatic tissues by various enzymes to a variety of metabolites. It follows then that during pre-clinical safety testing of drug candidates, within a given pre-clinical species, it is not only the parent drug that needs to be tested for its pharmacological and toxicological effects, but also its metabolites. Due to species-, strain-and sometimes sex-specific isoforms of enzymes and/or capacities, each drug has the potential to generate unique or disproportionate amounts of drug metabolites.

Disproportionate metabolite – when a metabolite is produced at significantly higher extent in humans than in pre-clinical safety species.

Unique human metabolite – when a metabolite is exclusively produced in humans.

Based on the FDA and ICH guidances, metabolites generated in humans after repeated dosing (at steady state of parent) must be evaluated with regard to their exposures in pre-Clinical safety species.

The FDA guidance (CDER. Guidance for Industry: S...) on metabolites in safety testing provides recommendations to industry on when and how to identify and characterize drug metabolites whose nonclinical toxicity needs to be evaluated.

In the ICH M3 guidance (M3(R2) Guidance on Non-clinica...) recommendations are found that further harmonise the nonclinical safety studies to support the various stages of clinical development among the regions of European Union (EU), Japan, and the United States.