Safety Profile Based on Concordance of Nonclinical Toxicity and Clinical Adverse Drug Reactions for Blood Cancer Drugs Approved in Japan.

BACKGROUND: In drug development, animal toxicology data are very important for the evaluation of clinical safety. We quantitatively assessed the safety profiles of blood cancer drugs approved in Japan from category I (high) to V (low). We examined the ratios of drug exposure in animals at the no observed adverse effect level to those in humans at the expected therapeutic dose. In addition, qualitative analysis of the relationship between toxicological findings and adverse drug reactions (ADRs) is one of the primary approaches for determining the risk-benefit profile of a pharmaceutical. This study thus aimed to evaluate the potential of nonclinical safety assessments for predicting ADRs in humans. METHODS: We examined toxicological findings at the lowest observed adverse effect level and ADRs in pivotal clinical studies. We calculated concordance rates as the ratio of the number of concordant ADRs to all ADRs. RESULTS: Twenty-seven drugs were eligible for analysis. Concordance rates ranged from 0 to 84.8%. No significant differences were observed in concordance rates between antibodies (median 14.3%) and small molecules (median 18.5%). There was a significant correlation between concordance rates and quantitative safety profiles (p = 0.047), suggesting that some drugs with low safety profiles (categories III, IV, or V) have high concordance rates. CONCLUSION: The results suggested that ADRs in clinical trials could be predicted based on toxicity data obtained in animal tests, especially for some drugs with a low quantitative safety profile.

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 (Cmax 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 Cmax 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.