Carcinogenicity Studies

Carcinogenicity studies involve the treatment of rodents for long periods of time (18 months to 2 years) in order to determine whether the material possesses the capability to initiate or promote the development of tumors. The relevance of these models to the human situation has been debated for many years. Carcinogenicity studies have been required for all drugs where clinical therapy may extend for 6 months or longer. While the scientific debate about relevance of these studies continues, they remain required by regulation.

Several different ICH guidelines have been issued that address the various aspects of the car-cinogenicity testing of drugs, including when studies are needed (duration of clinical therapy; Federal Register March 1 1996). Other features of the new drug may mandate carcinogenicity testing, such as structure-activity similarities to known carcinogens, evidence of preneoplastic lesions in repeated-dose non-clinical studies, or long-term tissue sequestration of the drug. Another guideline (Federal Register March 1 1995) addresses the complex issue of the selection of doses for these studies; this responds to much criticism of the prior recommendation to use the maximum tolerated dose (which had been suggested by the National Toxicology Program; Haseman and Lockhart 1994). The current ICH guideline recommends a high dose causing up to a 25-fold greater plasma AUC in rodents compared to the AUC in man at steady state. A subsequent amendment to this guideline (Federal Register December 4 1997) adds a further proviso that the highest dose in a carcinogenicity study need not exceed 1500 mg/kg/day when (a) there is no evidence of genotoxicity and (b) the maximum recommended human dose is no bigger than 500 mg/day. The basis for species selection, circumstances needing mechanistic studies, and exploitation of pharmacokinetic information in car-cinogenicity testing is described in yet another guideline (Federal Register August 21 1996).

Modern protocols for carcinogenicity studies have changed little since first established in the early 1970s. In recent years, the use of mice (historically the second of the two required species in addition to rats) has come under scrutiny because they may be inappropriate models, with unusual sensitivity to certain classes of chlorinated hydrocarbons. The most recent ICH guideline (Federal Register August 21 1996) allows for the option of using transgenic mice and study designs of somewhat shorter duration.

Of growing importance is the interaction of factors that are critical to a successful toxicology programme. For example, if a transgenic mouse model is selected, then the choice of strain is important and may depend upon whether the drug is non-genotoxic (TG.AC model) or genotoxic (p53 model). Metabolic and pharmacokinetic data are important to ensure that the selected models handle and metabolize the drug in a fashion at least rea sonably similar to man, and may vary for the same drug according to the toxic effect of interest. Perhaps the most important factor is the relevance of the doses selected to those in man. While this has been a subject of controversy for years, a recent ICH guideline allows for the use of toxicokinetic measurements, and states that doses that produce an AUC in the carcinogenicity model that are 25 times that seen in man at steady state may no longer have to be used under some circumstances. A recent review of the status of carcinogenicity testing (Reno 1997) addresses the many factors that should be considered in a carcinogenicity program.

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