Nonclinical toxicity study

It is essential to determine the concentration of each isomer and define limits for all isomeric components, impurities, and contaminants of the compound tested preclin-ically that is intended for use in clinical trials. The maximum level of impurities in a stereoisomeric product used in clinical studies should not exceed that in the material evaluated in nonclinical toxicity studies. This point is expanded in the ICH impurities guideline (Section 13.5.3). 

For FTIH trials, all applications should include a summary of projected free plasma concentrations of the new active substance (NAS) in humans and a brief description of any pharmacokinetic modelling programs used to generate the estimates. A comparison with the concentrations obtained in the nonclinical toxicity studies and projected safety margins should be given. In the same section, an estimate of the extent of the intended pharmacological or pharmacodynamic response at the expected plasma concentrations should be included, with a list of the assumptions used in deriving that estimate. 

There are 10 prime areas of a nonclinical toxicity study that must be examined. 

Those GLP violations that compromised or potentially compromised the scientific and hence the regulatory merit of a nonclinical toxicity study were classified VAI-3. Those inspections that prior to December 1993 were VAI-3 are now classified as OAI. 

Toxicokinetics is defined as the generation of pharmacokinetic data, either as an integral component in the conduct of nonclinical toxicity studies or in specially designed supportive studies, in order to assess systemic exposure. These data may be used in the interpretation of toxicology findings and their relevance to clinical safety issues (ICH Guidance Toxicokinetics 1994). 

Along with toxicity results, providing information on the appropriate design for subsequent nonclinical toxicity studies and human clinical studies... 

The function of clinical chemistry in toxicology (as well as in human and veterinary medicine) is to provide, via laboratory analysis, evaluations of the qualitative and quantitative characteristics of specific endogenous chemical components present in samples of blood, urine, feces, spinal fluid, and tissues. The purpose is to help identify abnormal or pathological changes in organ system functions. The most common specimens used in clinical chemistry are blood and urine, and many different tests exist to test for almost any type of chemical component in blood or urine for example, blood glucose, electrolytes, enzymes, hormones, lipids (fats), other metabolic substances, and proteins. The tests used were all initially applied to human clinical medicine, and may not possess the same utility when performed as part of nonclinical toxicity studies in a wide variety of other species. 

The described three cases address stimulation of the immune system by vaccines and/or adjuvants that could theoretically lead to adverse effects, including the potential induction of a systemic inflammatory response by new molecular adjuvants, T cell-mediated cytotoxicity by therapeutic vaccines, and autoimmunity by therapeutic cancer vaccines. In each case, the risk can be evaluated via appropriate assessments in nonclinical toxicity studies and by considerations of the relevance of the animal models to humans. 

There are cases when a dedicated CV telemetry study may be the best option to assess target liability concerns for BPs. These include the presence of the therapeutic target in the CV system (e.g., cardiac myocytes, vascular endothelium, or vascular smooth muscle) or the emergence of CV findings in nonclinical toxicity studies or clinical trials. For example, observation of cardiac dysfunction in patients treated with trastuzumab, a mAb for treatment of breast cancer, prompted the sponsor to perform a long-term telemetry study in the cynomolgus monkey in attempts to model the human cardiac dysfunction (Klein and Dybdal 2003). Likewise, a novel ADC based on trastuzumab was evaluated in a dedicated NHP telemetry study to evaluate potential target-mediated CV effects (Poon et al. 2013). 

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