@article{oai:dwcla.repo.nii.ac.jp:00001415,
 author = {伊賀, 勝美 and IGA, Katsumi},
 journal = {総合文化研究所紀要, Bulletin of Institute for Interdisciplinary Studies of Culture Doshisha Women’s College of Liberal Arts},
 month = {Jul},
 note = {application/pdf, AN10052143-20160715-124, I encountered several drugs terminated at the clinical development stage because of their unusual reactive-metabolite-involved pharmacokinetic (PK) behaviors when I worked for Takeda Chemical Ind. as a general research manager of their PK study of new chemical entities from 2000 to 2005. In this paper, in order to clarify the true causes of theirtermination, I chose three typical compounds (Compounds A, B, and C) and analyzed their preclinical and clinical PK data in the light of current scientific findings on reactive-metaboliteinduced unusual PK, retrospectively. Additionally, I analyzed the data on pioglitazone and alogliptin, drugs currently used for the treatment of type-II diabetes worldwide, from the same view as above.
 As a result, I found that the three compounds would never have been selected as candidates for clinical development, but would have been screened out at earlier optimization stages, in the light of the guidance published by Food and Drug Administration (FDA) in 2009 regarding Metabolite in Safety Testing (MIST). As for pioglitazone and alogliptin, I found a lack of sufficient data to show their safety for long-term usage.
 I also identify the following factors as key to success in drug development:
 (i) Chemical design as a function of medical dose and treatment period
 (ii) Clarification of risk and benefit of newly developed medical treatment
 (iii) Differentiation of drug efficacy and PK of reactive metabolites
 (iv) Optimization of new chemical entities after entering the clinical stages (feedback from clinical development to research)
 (v) Specification of places (organs or tissues) where unusual tissue damages occur due to a reactive metabolite
 (vi) Reactivity of a reactive metabolite over metabolic de-toxicity, particularly in the disease states
 (vii) Carcinogenicity of a reactive metabolite
 (viii) Additional clinical safety study (even after marketed), as required by the FDA, 論文},
 pages = {124--141},
 title = {新薬候補化合物の開発段階で見られた反応性代謝物による異常な薬物動態特性についての検証},
 volume = {33},
 year = {2016},
 yomi = {イガ, カツミ}
}