Evaluation of Safety Profiles of Blood Cancer Drugs Approved in Japan.

Background: In drug development, the safety of a test drug for human use is first assessed in animal toxicology studies; therefore, the no-observed-adverse-effect-level (NOAEL) and toxicokinetic data are very important for the evaluation of clinical safety. The ratio of drug exposure in animals at the NOAEL to that of humans at the expected therapeutic dose is one of the primary measures for determining the risk-benefit profile of a pharmaceutical. The objective of this study was to evaluate the safety profiles of drugs for blood cancer approved in Japan by examining safety indices (SIs).

Methods: SIs were calculated as animal-to-human ratios in doses and exposure using NOAEL, severely toxic dose 10% of the animals, highest nonseverely toxic dose, maximum approved dose, and exposure levels (C and area under the curve [AUC]) at the NOAEL and maximum approved dose. If the SI of a certain drug is <1.0, either the maximum therapeutic dose exceeds the NOAEL, or the exposure level at the maximum therapeutic dose exceeds the exposure level at the NOAEL.

Results: A total of 8 of 17 SIs by dose were <1.0; 6 of 8 SIs by C were <1.0, and 6 of 9 SIs by AUC were <1.0.

Conclusions: In cases where the SI is <1.0, no drug safety margin can be assured based on animal data. When extrapolating data from animal studies to safety assessment in clinical studies, safety profile would be one of aspects to be carefully considered in drug development, including postmarketing surveillance.