ADME and DMPK
Pharmacokinetics (PK) is the assessment of drugs in the body over time, including the processes of absorption, distribution, metabolism and excretion (ADME). It allows identification of target accumulation sites, maximum concentration times and routes of elimination. The pharmacokinetic properties of drugs are affected by elements such as the formulation, administration route, dose-level and administration period. Pharmacokinetics is a quantitative assessment which complements pharmacodynamics, where drug interactions with biological targets and the follow-up effects are assessed.
The analysis of biomarkers in preclinical and clinical studies is considered by both the EMA and the FDA as an important method to reduce costs, and speed up the development process. Various biomarker identification methods based on molecular profiling techniques are available, such as transcriptomics, proteomics and metabolomics.
Carcinogenicity and transgenic models
Carcinogenicity studies in rodents and transgenic mouse models are performed to identify any oncogenic potential for risk-assessment in humans. Any cause for concern derived from laboratory investigations, animal toxicology studies or data in humans may lead to a requirement for carcinogenicity studies. In the case of drugs intended for life-long administration, the potential for a carcinogenic effect of long term exposure can also be evaluated.
To learn more see : carcinogenicity, mouse and rat studies, transgenic models, carcinogenicity for chemicals, carcinogenicity for medical devices, carcinogenicity for novel food, ingredients and additives
Clinical pathology aims to determine hematological, biochemical, coagulation and urinary parameters during preclinical studies and can help identifying biomarkers relevant for clinical studies. Flow cytometry-based assays can help to characterized blood and tissues immunophenotyping and to follow surface and intracytoplasmic biomarkers during in vivo or in vitro studies.
One of the objectives of developmental and reproductive toxicology is to assess potential adverse effects induced during gametogenesis, gestation and/or post-natal development (including premature, new-born and infant, child and adolescent periods). As these can appear at any point, from reproductive ability of the parent generation, through embryo-fetal and juvenile development, to effects on the first or second generation, DART covers fertility, peri-postnatal , juvenile and multigeneration studies. Teratogens and endocrine disruptors are part of well-known group of substances which are toxic for reproduction.
To learn more see : Uterotropic assays, Hershberger assays, Neuro‑histomorphometry, DART in general, fertility, peri-post-natal studies, juvenile studies, one and two generation studies, Developmental toxicology for pharmaceuticals and biopharmaceuticals, reproductive toxicology for chemicals, reproductive toxicology for medical devices, reproductive toxicology for food
Dermal toxicity is the ability of a substance to cause adverse effects on living organisms by contact with the skin. Toxic compounds may be absorbed through the skin to various degrees, depending on their chemical composition, concentration and whether they are dissolved in a solvent. Specialized techniques coupled with analytical chemistry methods are used to measure dermal toxicity.
To learn more see : dermal services
Toxicology is the study of adverse effects on living organisms. It is the assessment of symptoms, mechanisms and any harmful effects caused by the administration or exposure to exogenous compounds in biological systems. The dynamics of distribution, metabolization and excretion are evaluated (clinical signs, hematology, gene expression, histopathology, etc.) to identify target organs, biomarkers, metabolite activity and systemic toxicity, and to evaluate potential effects on physiological parameters. Dose Range Finding studies (DRF) are performed to determine dose levels at which there are adverse effects and no adverse effects.
Genotoxicity studies assess potential damage to the genetic information (DNA) of cells. Damage, which can potentially lead to the formation of cancer. Chemicals can cause base mutations and deletions, damage to chromosomes or disruption of the processing of genetic information during cell division. Identifying these risks early for new drugs or chemical agents is a key step in development.
To learn more see : genetic toxicology in general, genetic toxicology for chemicals, genetic toxicology for cosmetics, genetic toxicology for medical device, genetic toxicology for food ingredients and additives
Immunohistochemistry (IHC) refers to the process of detecting antigens in/on the cells of biological tissue sections by exploiting the principle of antibodies binding specifically to antigens. IHC staining is widely used for the characterization of inflammatory process, identification of cells involved in a pathological lesion or to highlight particular cellular events, such as proliferation or apoptosis. IHC is also widely used to understand the distribution and localization of biomarkers and expressed proteins in different parts of a biological tissue.
Tissue cross reactivity studies aim to identify on- and off-target fixations of a therapeutic antibody (or related) on tissues from humans and/or animals.
Immunotoxicology can be defined as the study of potential adverse effects on the immune system or of the immune system on other tissues and organs resulting from exposure to physical factors (e.g. ionizing), chemicals (including drugs), biological materials, medical devices and, in certain instances, physiological factors. It encompasses studies of various immune pathologies associated with exposure to molecules that cause reactions such as allergy, immune deregulation (suppression or enhancement), autoimmunity and chronic inflammation.
The determination of sub-acute to chronic inhalation toxicity is an essential step in the assessment of an inhalable material, such as a gas, volatile substance or aerosol/particulate. It provides information on health hazards likely to arise from short-term exposure by inhalation.
To learn more see : inhalation toxicology
At CiToxLAB, histopathology is performed by board certified veterinary pathologists (ACVP and ECVP), specialized in the identification and interpretation of macroscopic and microscopic findings. Pathologists play an important role in drug discovery and safety evaluation.
Ocular toxicity studies investigate the potential toxicity of ophthalmological compounds after application or injection of the compound. Local tolerance ocular irritation studies evaluate the potential adverse effects of chemicals in the eye and associated mucous membranes to provide information on health hazards likely to arise in humans during use.
The objective of radiation safety is principally to measure Acute Radiation Syndrome (ARS) caused by exposure of the body to radiation: radiolabelled compounds for therapies such as oncology, new technologies using ionizing radiation, accidents, and nuclear medicine. It is divided into three major forms that are, in ascending order of severity, hematological, gastrointestinal, and CNS‑cardiovascular forms.
To learn more see : radiation safety and efficacy models
REACH and ecotoxicology
REACH is the European Union (EU) regulation on the Registration, Evaluation, Authorization and restriction of Chemicals. The aim of REACH is to ensure a high level of protection for human health and the environment. CiToxLAB proposes a full range of ecotoxicology and biodegradation studies to evaluate potential risks. REACH regulation also suggest the use of alternative test methods.
Safety pharmacology studies are a key requirement in the drug development process. The impact on vital organ systems of new chemical entities (NCE) or biotechnology-derived products is assessed before first-in-man drug testing. Safety pharmacology studies investigate potential undesirable pharmacodynamic effects of a substance on physiological functions: cardiovascular, central nervous system, respiratory, renal, gastro-intestinal, etc.
Tissue cross reactivity
Tissue cross reactivity (TCR) studies are screening assays designed to identify test article binding activity (i.e., antibody or antibody-like protein) in tissues. The main objective is to identify binding to unexpected targets (i.e., cross-reactive epitopes), hence the term cross-reactivity. CiToxLAB can test your drug candidate on the full FDA and EMEA tissue list, in human and all preclinical species. All tissue biobanks are checked and validated for morphology and immunoreactivity. Tissue cross reactivity studies are conducted prior to clinical trials. Results are filed with the initial IND/CTA to support first-in-human clinical trials.
Toxicogenomic studies investigate the impact of xenobiotics on the transcriptome (mRNA and miRNA) of a cell or tissue. Understanding the impact of xenobiotics on biological pathways allows the prediction of adverse events and a greater understanding of the effect of potential drugs on an organism. Toxicogenomic studies require advanced data analysis (bioinformatics) and an in depth understanding of cell biology.
In vitro toxicology
In vitro toxicology is the study of potential adverse effects of compounds on cultured cells in simple 2D or 3D cell models. In vitro testing methods are used to identify hazards in the development of chemicals, pharmaceuticals, agrochemicals, cosmetics, medical devices and food ingredients. The development of new in vitro alternative approaches to animal testing is an integral part of our dedication to the 3Rs philosophy (Replacement, Reduction and Refinement). CiToxLAB has recently been elected as an EU-NETVAL qualified laboratory.