General aspects of PCS

  • Serves early as research support (mainly non-GLP) for selection of compounds and later as development support (mainly for GLP regulatory studies)
  • Subdivided into the following main specialties (selection):
    • In-life investigations
    • Clinical pathology including biomarkers, etc.
    • Investigations of absorption, distribution, metabolism and excretion (ADME)
    • Toxicologic pathology including necropsies and histopathological investigations
    • Other areas such as technical research and development (formulation, CMC documentation, etc.)
  • Type of investigations:
    • In silico: computer programs, particularly during very early stages
    • In vitro: studies in cell cultures, especially for investigation of genotoxicity
    • In vivo: animal studies

Objectives:

  • Safety before first-in-human (FIH) clinical trials and starting dose for FIH clinical studies
  • Further assurance of non-clinical safety of substances, partly in parallel to clinical testing during increasing time periods

Assurance of safety reached by studying the following:

  • General toxicity: acute (single dose), subacute (up to 1 month), subchronic (up to 3 months), chronic (up to 9 months). In vivo, generally in a rodent (rat) and a non-rodent species (dog or minipig)
  • Carcinogenicity, also called life-time studies. Carcinogenicity can also occur without demonstratable mutagenicity. In vivo, generally in two rodent species (rat and mouse)
  • In vitro and in vivo, the latter generally in rodents (rat)
  • Safety pharmacology, generally of the cardiovascular system (in vitro e.g. hERG test, in vivo non-rodent electrocardiogram ECG), behavior (in vivo, rodents – generally rats) and respiratory (in vivo, rodents – generally rats, plethysmography, but observation is often sufficient)
  • Reproductive toxicity (fertilization, pregnancy, postnatal development), generally in vivo in rodents (rats); exception pregnancy testing: one rodent (rat) and one non-rodent species (rabbit)

See in particular also chapters on Animals used in preclinical safety and Designs of preclinical safety studies.

Importance (selection) of

  • Peer review in particular for histopathological evaluation
  • Historical data particularly of post-mortem and histopathological findings as well as of potential teratogenic effects

Modifying factors include differences between test animals and humans regarding health status, maturity (in particular of sexual development), ADME behavior, etc. See chapter on Animals used in preclinical safety.

Populations exposed to chemicals and drugs are infants and children (and other categories of young adults), adults and elderly people. The people exposed may differ in their health status (from healthy to various diseases), etc. See also Regulations – References.

For a risk assessment, in particular the following parameters need to be considered:

  • Severity of the disease foreseen for treatment
  • Age of the target population exposed
  • Experience with similar drugs
  • Differences between test animals and humans (see also chapter Animals used in preclinical safety)

Shorter presence in the body, that is higher excretion, is often an advantage in case of a (possibly) compound-associated adverse effect.