Development of individualized medicine by exposure matching based on key determinant of pharmacokinetics

• Project/Area Number: 17K08961
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Applied pharmacology
• Research Institution: Showa University (2018-2020); Keio University (2017)
• Principal Investigator: IMAMURA Chiyo 昭和大学, 大学共同利用機関等の部局等, 准教授 (00570954)
• Co-Investigator(Kenkyū-buntansha): 谷川原 祐介 慶應義塾大学, 医学部(信濃町), 教授 (30179832)
• Project Period (FY): 2017-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2017: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000)
• Keywords: 個別化投与 / 薬物曝露量 / 薬物動態 / PK規定因子 / がん薬物療法 / 個別化投薬 / exposure matching

Outline of Final Research Achievements

Our previous pharmacokinetic study in 16 cancer patients with various renal functions developed an S-1 dosage formula based on individual creatinine clearance (CLcr) and body surface area (BSA). To evaluate and refine the formula, this prospective study was conducted. The revised nomograms for recommended daily doses derived from the refined formula can be used in clinical practice to achieve the target AUC ensuring efficacy and safety of S-1.
Regorafenib and its active metabolites of M2 and M5 are extensively bound to the serum proteins. We found that the serum unbound concentrations of the sum of regorafenib and the active metabolites correlated significantly with the maximum grade of regorafenib-related symptomatic adverse events in the first cycle. There were no association between their unbound fractions and the serum albumin levels, which is their major binding protein.

Academic Significance and Societal Importance of the Research Achievements

欧米ではFDAやEMAの製薬企業向けガイドラインにより、医薬品開発時には腎機能低下者での薬物動態試験を実施し、その結果に基づき腎機能低下患者への用量調節指針が示されている。しかしS-1は米国では承認されておらず、また欧州での承認用量はシスプラチンとの併用による50mg/m2/日のためアジアでの承認用量80mg/m2/日とは異なっており、日本を含むアジアでの承認用量においては腎機能低下者での曝露量増加データに基づいた用量調節指針が存在していない。したがって本研究にて改訂されたノモグラムは、S-1の個別化投与のためのツールとして有効性と安全性の担保されたがん薬物療法の実践に貢献できると考えている。

Research Products

• [Journal Article] Prospective evaluation and refinement of an S-1 dosage formula based on renal function for clinical application. (2021)
  • Author(s): Takeuchi M, Imamura CK, Booka E, Takeuchi H, Mizukami T, Kawakami T, Funakoshi T, Wakuda K, Aoki Y, Hamamoto Y, Kitago M, Kawakubo H, Boku N, Tanigawara Y, Kitagawa Y.
  • Journal Title: Cancer Science Volume: 112 Issue: 2 Pages: 751-759
  • DOI: 10.1111/cas.14758
  • Peer Reviewed / Open Access
• [Journal Article] A phase II study of regorafenib with a lower starting dose in patients with metastatic colorectal cancer: exposure-toxicity analysis of unbound regorafenib and its active metabolites (RESET Trial). (2020)
  • Author(s): Suzuki T, Sukawa Y, Imamura CK, Masuishi T, Satake H, Kumekawa Y, Funakoshi S, Kotaka M, Horie Y, Kawai S, Okuda H, Terazawa T, Kondoh C, Kato K, Yoshimura K, Ishikawa H, Hamamoto Y, Boku N, Takaishi H, Kanai T.
  • Journal Title: Clinical Colorectal Cancer Volume: 19 Issue: 1 Pages: 13-21
  • DOI: 10.1016/j.clcc.2019.10.004
  • Peer Reviewed
• [Presentation] Exposure-toxicity analysis of unbound regorafenib and its active metabolites by dose escalation strategy with low starting dose in patients with colorectal cancer. (2019)
  • Author(s): Satake H, Suzuki T, Imamura CK, Sukawa Y, Satake H, Kumekawa Y, Funakoshi S, Kotaka M, Horie Y, Kawai S, Okuda H, Terazawa T, Kondoh C, Kato K, Yoshimura K, Ishikawa H, Hamamoto Y, Boku N, Takaishi H, Kanai T.
  • Organizer: AACR Annual Meeting
  • Int'l Joint Research
• [Presentation] Exposure-response analysis of S-1 in patients with advanced gastric cancer. (2019)
  • Author(s): Takeuchi M, Imamura CK, Booka E, Kasai H, Kawakubo H, Boku N, Tanigawara Y, Kitagawa Y.
  • Organizer: 第17回日本臨床腫瘍学会学術集会
• [Presentation] Prospective evaluation of a developed S-1 dosage formula based on renal function. (2019)
  • Author(s): Mizukami T, Takeuchi M, Imamura CK, Booka E, Takeuchi H, Kawakami T, Funakoshi T, Wakuda K, Aoki Y, Hamamoto Y, Kitago M, Kawakubo H, Boku N, Tanigawara Y, Kitagawa Y
  • Organizer: ASCO Gastrointestinal Cancers Symposium
  • Int'l Joint Research
• [Presentation] 腎機能に基づくS-1用量算出式「B-B formula」の検証試験 (2019)
  • Author(s): 竹内優志，今村知世，坊岡英祐，竹内裕也，水上拓郎，川上武志，浜本康夫，川久保博文，朴成和，谷川原祐介，北川雄光
  • Organizer: 第52回制癌剤適応研究会
• [Presentation] Prospective evaluation of regorafenib dose escalation strategy with low starting dose in patients with colorectal cancer. (2018)
  • Author(s): Masuishi T, Suzuki T, Sukawa Y, Imamura CK, Satake H, Kumekawa Y, Funakoshi S, Kotaka M, Horie Y, Kawai S, Okuda H, Terazawa T, Kondoh H, Kato K, Yoshimura K, Ishikawa H, Hamamoto Y, Boku N, Kanai T, Takaishi H
  • Organizer: ESMO 2018 Congress
  • Int'l Joint Research
• [Presentation] Impact of CYP2C19 polymorphisms on the pharmacokinetics of tacrolimus when co-administered with voriconazole (2017)
  • Author(s): 今村 知世
  • Organizer: 15th International Congress of Therapeutic Drug Monitoring & Clinical Toxicology
  • Int'l Joint Research
• [Presentation] 腎障害患者における抗がん薬のPK/PDと用量調節 (2017)
  • Author(s): 今村 知世
  • Organizer: 第9回日本がん薬剤師学会
  • Invited
• [Presentation] 抗がん薬の臨床薬理 (2017)
  • Author(s): 今村 知世
  • Organizer: 第55回日本癌治療学会学術集会
  • Invited
• [Remarks] 昭和大学先端がん治療研究所
  • URL: https://www.showa-u.ac.jp/research/act/achievement/