title: Perspectives on non-clinical safety evaluation of drug metabolites through the JSOT workshop.
abstract: The prompt and appropriate safety assessment of drug metabolite(s) was mentioned in regulatory guidances such as an International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) guidance, entitled "Guidance on Non-clinical  Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals" (ICH M3(R2)) implemented in January 1 of 2011 in Japan, and has become a significant issue in the drug development. Upon release of ICH M3(R2) Step 4, a survey was conducted between March and April 2010 on the safety assessment of drug metabolites in 63 member companies of the Japan Pharmaceutical Manufacturers Association (JPMA). The Pharmacokinetics Team in the Non-Clinical Evaluation Expert Committee in JPMA conducted a questionnaire survey and compiled the results to comprehend how safety of drug metabolites are currently assessed at research-based pharmaceutical companies in Japan. The assessment of "Metabolites in Safety Testing" (MIST) can be divided into three stages based on the research purpose as follows: MIST 1 is a stage of estimating human drug metabolites and predicting their potential risks, MIST 2 is a stage of deciding the necessity for non-clinical safety studies, and MIST 3 is a stage of conducting non-clinical safety studies. In this paper, we propose typical approaches on safety assessment of metabolites that meet the purpose of each stage, considering the current level of scientific technology. Our proposals are based on the results from our survey and a symposium about the safety assessment of drug metabolites at the 37th annual meeting of the Japanese Society of Toxicology held in June 2010.
authors.affiliation: Non-Clinical Evaluation Expert Committee, Drug Evaluation Committee, Japan Pharmaceutical Manufacturers Association, Tokyo, Japan. t.minagawa@po.rd.taisho.co.jp
authors.forename: Toshiya
authors.initials: T
authors.lastname: Minagawa
authors.forename: Kenji
authors.initials: K
authors.lastname: Nakano
authors.forename: Shigeru
authors.initials: S
authors.lastname: Furuta
authors.forename: Takashi
authors.initials: T
authors.lastname: Iwasa
authors.forename: Koji
authors.initials: K
authors.lastname: Takekawa
authors.forename: Kouichi
authors.initials: K
authors.lastname: Minato
authors.forename: Toshihisa
authors.initials: T
authors.lastname: Koga
authors.forename: Takashi
authors.initials: T
authors.lastname: Sato
authors.forename: Kosuke
authors.initials: K
authors.lastname: Kawashima
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Kurahashi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Onodera
authors.forename: Shinsaku
authors.initials: S
authors.lastname: Naito
authors.forename: Kazuichi
authors.initials: K
authors.lastname: Nakamura
mesh_terms: D000818:Animals; D004353:Drug Evaluation, Preclinical / Q000592:standards*; D004347:Drug Interactions; D017408:Guidelines as Topic; D006801:Humans; D007564:Japan; D004364:Pharmaceutical Preparations / Q000032:analysis; D018570:Risk Assessment; D014481:United States; D014486:United States Food and Drug Administration
chemical_list: D004364:Pharmaceutical Preparations