Dose selection for carcinogenicity studies of pharmaceuticals: systemic exposure to phenacetin at carcinogenic dosage...

A systemic exposure-based alternative to the MTD (maximally tolerated dose) for high-dose selection in carcinogenicity studies of pharmaceuticals has been accepted by the ICH (International Conference on Harmonisation of Technical Requirements for the Registration of Pharmaceuticals for Human Use). As a result of a retrospective analysis performed by the U.S. FDA (United States Food and Drug Administration), a rat/human relative systemic exposure ratio of 25 is proposed by the ICH as an acceptable pharmacokinetic endpoint for high-dose selection. For use as a dose selection criterion, it is particularly important that the magnitude of the relative systemic exposure ratio should be sufficient to detect human pharmaceuticals classified by IARC (International Agency for Research on Cancer, World Health Organization) as known (category 1) or probable (category 2A) human carcinogens. For one of these, phenacetin (an IARC 2A compound and a rat carcinogen), a systemic exposure ratio of 15 was calculated by the FDA. This calculation was based on a number of extrapolations. The present study reports the actual systemic exposure to phenacetin in the rat under conditions mimicking the conditions in the carcinogenicity study used by the FDA to calculate the relative systemic exposure ratio of 15. The ratio was found to be 7, indicating that the carcinogenic potential of this particular probable human carcinogen could be detected at a considerably lower systemic exposure ratio than that proposed by the ICH.