Abstract
A systemic exposure-based alternative to the maximum tolerated dose (MTD) for high-dose selection in carcinogenicity studies for human therapeutics was accepted at the Second International Conference on Harmonization (ICH-2). The systemic exposure-based alternative to the MTD is suitable for nongenotoxic compounds with low rodent toxicity that are metabolized similarly in rodents and humans. This is the first product of an evaluation of current standards for rodent carcinogenicity studies of therapeutics. The relative systemic exposure is the ratio of the rat plasma area under the plasma concentration-time curve (AUC) at the MTD/human plasma AUC at the maximum recommended daily dose. An appropriate systemic exposure ratio for high-dose selection in carcinogenicity studies was empirically derived from the distribution of systemic exposure ratios attained by 35 compounds from 11 therapeutic categories in a Food and Drug Administration (FDA) database. Approximately one-third achieved a relative systemic exposure ratio <1 and two-thirds attained an exposure ratio of 10 or less, at the MTD. A systemic exposure ratio of at least 25 was accepted for high-dose selection in carcinogenicity studies at ICH-2. This ratio is high enough to detect all compounds with positive studies in the FDA database and would detect IARC 1 and 2A carcinogenic drugs. A ratio of 25 exceeds the systemic exposure ratio attained by 75% of drugs tested at the MTD in the FDA database and represents an adequate margin of safety which can be attained by a significant proportion of drugs.