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

2020 Fiscal Year Final Research Report

• 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
• 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

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.

Free Research Field

臨床薬理

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。