Safety pharmacology test systems

Additional digestive system safety pharmacology tests include effects of test articles on gastric emptying rate and gastric secretion. Gastric... 

As mentioned previously, the preliminary focus of safety pharmacology studies is to measure the effects of the test substance on the cardiovascular, respiratory and central nervous systems. 

The purpose of the safety pharmacology core battery is to investigate the effects of the test substance on vital functions. In this regard, the cardiovascular, respiratory and central nervous systems are usually considered the vital organ systems that should be studied in the core battery. In some instances, based on scientific rationale, the core battery may need to be supplemented (see also section 2.8) or may not need to be implemented (see also section 2.9). 

Safety pharmacology studies in rodent and nonrodent These studies are designed to identify undesirable pharmacological effects in several systems primarily the cardiovascular, respiratory, and CNS systems. Other studies may be included based on the pharmacological activity of the test article. In many cases these studies are not required for biopharmaceuticals and/or may be included in the 4- and 13-week studies and 6- and 9-month studies. 

The methods described here are applied for Supplemental Safety Pharmacology Studies (ICH S7A), if the test substance has shown indications of effects on the hypothalamic-pituitary-adrenal system in the preceding pharmacology studies. The in vitro studies are generally performed with several increasing doses to investigate concentration-effect relationships. The preliminary information from these in vitro studies is then compared with the biological information available from in vivo for studies, to assess the need for additional animal studies based on repeated dose administration of the test compound. 

In the safety pharmacology protocol, the interaction of multiple endocrine systems in test animals is addressed. As discussed by Harvey (1996) and by Harvey and Everett (2003), effects on adrenocortical function are frequently found in toxicology studies, sometimes related to enzyme induction and effects on steroid biosynthesis (Loose et al. 1983, Nebert and Russell 2002, Weber et al. 1993). Test procedures in animals are required when there is a reason for concern. Frequently however the effects observed are due to stress rather than specific interaction with the target organ, and may involve effects on catecholamine release from the adrenal medulla (Tucker 1996). Recently, much new evidence has been accumulated from the testing of industrial chemicals with effects on adrenal steroid biosynthesis (Harvey and Johnson 2002). 

S7A differentiates between 3 types of studies core battery, follow-up and supplemental studies. The core battery of tests/S7A consistes of an investigation of the effects of a test substance on vital functions central nervous system cardiovascular system respiratory system other systems as appropriate. The exclusion of a system or function should be justified. Safety Pharmacology studies carried out as necessary as ... 

Generally, any parent compound and its major metabolite(s) that achieve, or are expected to achieve systemic exposure in humans should be evaluated in safety pharmacology studies. Evaluation of major metabolites is often accomplished through studies of the parent compound in animals. Additionally, if metabolites from humans are known to substantially contribute to the pharmacological actions of the therapeutic agent, it may be important to test such active metabolites. 

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