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新薬候補化合物の開発段階で見られた異常な薬物動態特性についての検証：その２
https://doi.org/10.15020/00001759
https://doi.org/10.15020/0000175963f53f49-7b0e-48fd-a9b1-340bed6d0352
| 名前 / ファイル | ライセンス | アクション |
|---|---|---|
新薬候補化合物の開発段階で見られた異常な薬物動態特性についての検証：その２ (1.6 MB)
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| Item type | 紀要論文 / Departmental Bulletin Paper(1) | |||||
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| 公開日 | 2020-06-05 | |||||
| タイトル | ||||||
| タイトル | 新薬候補化合物の開発段階で見られた異常な薬物動態特性についての検証：その２ | |||||
| タイトル | ||||||
| タイトル | Retrospective analysis of unusual pharmacokinetics of new chemical entities observed in clinical development stages: II | |||||
| 言語 | en | |||||
| 言語 | ||||||
| 言語 | jpn | |||||
| 資源タイプ | ||||||
| 資源タイプ識別子 | http://purl.org/coar/resource_type/c_6501 | |||||
| 資源タイプ | departmental bulletin paper | |||||
| ID登録 | ||||||
| ID登録 | 10.15020/00001759 | |||||
| ID登録タイプ | JaLC | |||||
| 著者 |
伊賀, 勝美
× 伊賀, 勝美× Iga, Katsumi |
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| 著者 所属 | ||||||
| 値 | 同志社女子大学・薬学部・医療薬学科 | |||||
| 著者所属(翻訳) | ||||||
| 値 | Department of Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Doshisha Womenʼs College of Liberal Arts | |||||
| 抄録 | ||||||
| 内容記述タイプ | Abstract | |||||
| 内容記述 | Retrospective analysis of the unusual pharmacokinetic (PK) behaviors of four new chemical compounds of Takeda Chem. Ind. [compounds A, B, C, and ramelteon (RAM)] observed in the clinical development stages revealed interesting findings, which are summarized as follows: 1) High affinity of compound A to RBCs. The phase I study performed in those days, showed that compound A exhibits an unusually high value of blood-plasma ratio (Rb ~15) and non-linear PK characteristics were observed for the drug due to saturation in the distribution to RBCs. Ultimately, this compound was not advanced to the next phase. The author still approves of the decision, considering retinopathy induced by chloroquine. Both the drugs have the structure of a cationic amphiphilic drug (CAD). In general, a CAD tends to accumulate in the lysosomes in cells and induces cell lysis, and this characteristic is related to its high affinity to the RBCs. ADME studies performed by administering the radiolabeled compound to rats showed that the compound distributes to the orbits of the eyes at high concentrations for a long time period. Thus, it seemed reasonable to correlate the high affinity to RBCs to the cellular toxicity. 2) Variability in PK of compound B. The phase I study performed in those days showed that both the plasma levels of the unchanged drug and one of the metabolites (M-I) of the compound changed largely in response to the polymorphisms of one of the UDP-glucuronosyl transferases (UGT2B25). Because M-I was produced by CYP2C8-mediated oxidation of compound B, the variability in plasma M-I level appeared to be indifferent to the UGT polymorphisms. However, extensive PK analysis suggested that glucuronidation of the compound through UGTP2B25 is associated with CYP2C8 function and is essential for the oxidation of the compound to M-I. Unfortunately, this interplay between UGT and CYP2C8 in M-I formation has never been studied since the termination of the study. Nevertheless, in 2015 it was reported that one of the active metabolites of loratadine (a 2nd generation antihistamine) is produced by the same mechanism as for M-I formation. This report convinced us that the UGT-CYP2C8 interplay was responsible for the PK variability of compound B. 3) Difference in PK of compound C between rat and human and its relevance for pharmacological activity. The phase I study performed in those days showed that the Cmax and AUC of compound C after oral administration to humans were almost 20 and 50 times, respectively, more than those observed in rats, and the AUC was almost 10 times of that observed for TAK-475 (the preceding compound of the same class) and atorvastatin (marketed HMG-CoA reductase inhibitor) in humans. The clinical pharmacological activity, examined parallel to the PK study, was not as high as expected. In those days, the major cause of this insufficient activity was explained by the stronger plasma protein-binding of the compound in humans than expected, thereby decreasing the unbound active drug level in the liver as the target organ. Indeed, it was confirmed in the present study that species differences in the CLoral and Vdss of the compound can be successfully explained by the species difference in the blood unbound fraction (fub). However, theoretically, such a change in the fub must have little impact on the unbound drug level in the hepatic cells, relevant for the pharmacological activity of this compound, and it was suggested that the insufficient clinical pharmacological activity of the compound would owe largely to its intrinsic pharmacological activity. 4) Changes in plasma metabolite levels as observed in drug-drug interaction (DDI) between RAM and fluvoxamine (FLV). Usually, the analysis of DDI focuses on increases in the plasma unchanged drug levels. However, the present study analyzed the RAM-FLV DDI, focusing on the increases/decreases in the plasma levels of the multiple metabolites of RAM. The method assumed that the change in metabolite formation in response to DDI approximately equals to the change in the AUC/t1/2 of the metabolite. This approach would be helpful for the graphical analysis of the changes in the blood drug/metabolite levels due to DDI, and ultimately could allow more accurate and reliable prediction of DDI, when combined with the approach focusing on the increases in the unchanged drug levels. These findings on the PK characteristics seem be applicable to commonly used drugs. They would be useful for researchers developing new medicines. |
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| 内容記述 | ||||||
| 内容記述タイプ | Other | |||||
| 内容記述 | 論文 | |||||
| 書誌情報 |
総合文化研究所紀要 en : Bulletin of Institute for Interdisciplinary Studies of Culture Doshisha Women’s College of Liberal Arts 巻 35, p. 103-127, 発行日 2018-07-27 |
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| 出版地 | ||||||
| 出版者 | 京都 | |||||
| 出版者 | ||||||
| 出版者 | 同志社女子大学総合文化研究所 (学術研究支援課) | |||||
| ISSN | ||||||
| 収録物識別子タイプ | ISSN | |||||
| 収録物識別子 | 09100105 | |||||
| 書誌レコードID | ||||||
| 収録物識別子タイプ | NCID | |||||
| 収録物識別子 | AN10052143 | |||||
| 資源タイプ | ||||||
| 内容記述タイプ | Other | |||||
| 内容記述 | application/pdf | |||||
| ID | ||||||
| 内容記述タイプ | Other | |||||
| 内容記述 | AN10052143-20200605-103 | |||||
