Repeat-dose toxicity studies safety pharmacology assessments

In safety pharmacology, a number of renal functional tests, such as creatinine and electrolyte measurements, can be supported by most clinical chemistry laboratories (Kinter, Gossett, and Kerns 1994 Seuter 1996 ICH 2000). In some of the later chapters discussing assessments of hepatotoxicity and renal toxicity, a few functional tests are mentioned. Although it may be desirable to include function tests in repeated-dose toxicity studies, given the additional and sometimes invasive procedures, these tests may be better performed by incorporation into single-dose toxicity studies or separate additional studies (Matsuzawa et al. 1997). 

Therefore, in safety pharmacology, the first-tier test used is a neurobehavioural assessment, either in the format of the functional observational battery (FOB) or Irwin test (Moser 1989 LeBel and Foss 1996 Moser et al. 1997 Redfern et al. 2005 Roux et al. 2005 Redfern and Wakefield 2006). Similar assessments have been devised for dogs (Gad and Gad 2003 Tontodonati et al. 2007 Moscardo et al. 2009) and monkeys (Gauvin and Baird 2008 Moscardo et al. 2010 Froget et al. 2012). Where there is specific cause for concern arising from the knowledge of a compound, appropriate single-parameter tests can be incorporated into a repeat-dose toxicity study on a case-by-case basis to address the issue. Examples of suitable tests are listed in Table 3. 

Prior to beginning development, many sponsors would also have conducted in vitro safety pharmacology studies (e.g., hERG inhibition) to assess cardiovascular concerns, as well as single-dose and 5- to 7-day repeated-dose non-GLP-compliant studies to assess toxicity and help set doses for the GLP-compliant studies (see Table 7.3). 

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