title: Safety Profile Based on Concordance of Nonclinical Toxicity and Clinical Adverse Drug Reactions for Blood Cancer Drugs Approved in Japan.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Laboratory of Pharmaceutical Regulatory Science, Graduate School of Pharmaceutical Sciences, Josai International University, 1 Gumyo, Togane, Chiba, 283-8555, Japan. dp14-002@jiu.ac.jp.
authors.forename: Sachie
authors.identifier: http://orcid.org/0000-0002-6211-9061
authors.initials: S
authors.lastname: Kubota
authors.affiliation: Department of Development Strategy, National Center for Child Health and Development, Setagaya-ku, Tokyo, Japan.
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Saito
authors.affiliation: Laboratory of Pharmaceutical Regulatory Science, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Bunkyo-ku, Tokyo, Japan.
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Ono
authors.affiliation: Laboratory of Pharmaceutical Regulatory Science, Graduate School of Pharmaceutical Sciences, Josai International University, 1 Gumyo, Togane, Chiba, 283-8555, Japan.
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Kodama
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D017277:Drug Approval; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007564:Japan; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy*
chemical_list: D000970:Antineoplastic Agents