Prediction of lamotrigine clearance by using endogenous compounds as biomarker

• Project/Area Number: 18K06748
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 47060:Clinical pharmacy-related
• Research Institution: Okayama University
• Principal Investigator: Fujiyoshi Masachika 岡山大学, 医歯薬学総合研究科, 准教授 (50751921)
• Co-Investigator(Kenkyū-buntansha): 有吉 範高 岡山大学, 医歯薬学総合研究科, 教授 (00243957) ; 松本 准 岡山大学, 医歯薬学総合研究科, 助教 (60709012)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2020: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2019: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000); Fiscal Year 2018: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
• Keywords: ラモトリギン / バイオマーカー / 個別化医療 / てんかん / LC-MS/MS

Outline of Final Research Achievements

Lamotrigine is one of widely used anti-epileptic drugs, but it has a critical issue of a skin rush. The present study was performed to develop a method for the prediction of lamotrigine clearance. We developed a method for quantitation of 25-hydroxyvitamin D3 (25-OH-VD), an endogenous substrate for UGT1A4, and 25-hydroxyvitamin D3 3-glucuronide (25-OH-VD-glu). The ratio between the blood concentration of 25-OH-VD and 25-OH-VD-glu was correlated with lamotrigine clearance, suggesting the ratio might be a useful biomarker for prediction of lamotrigine clearance.

Academic Significance and Societal Importance of the Research Achievements

抗てんかん薬ラモトリギンによる皮膚障害は、死亡例も報告された重篤なものである。また、皮膚障害は蓄積毒性ではなく、単回服用でも出現する場合があり、ラモトリギンを服用する前に患者個々に投与量を適正化できる方法論の構築が必要である。本研究は、ラモトリギンクリアランスを薬剤を投与することなく予測できる方法論を提唱したものであり、ラモトリギンの適正使用推進につながると考えられる。

Research Products

• [Journal Article] Dasatinib can Impair Left Ventricular Mechanical Function But May Lack Proarrhythmic Effect: A Proposal of Non-clinical Guidance for Predicting Clinical Cardiovascular Adverse Events of Tyrosine Kinase Inhibitors. (2020)
  • Author(s): Izumi-Nakaseko H, Fujiyoshi M, Hagiwara-Nagasawa M, Goto A, Chiba K, Kambayashi R, Naito AT, Ando K, Kanda Y, Ishii I, Sugiyama A
  • Journal Title: Cardiovasc Toxicol. Volume: 20(1) Issue: 1 Pages: 58-70
  • DOI: 10.1007/s12012-019-09538-5
  • Peer Reviewed
• [Journal Article] Population Pharmacokinetics of Vancomycin under Continuous Renal Replacement Therapy using a Polymethylmethacrylate Hemofilter (2019)
  • Author(s): Yamazaki Shingo、Tatebe Mizuki、Fujiyoshi Masachika、Hattori Noriyuki、Suzuki Tatsuya、Takatsuka Hirokazu、Uchida Masashi、Suzuki Takaaki、Ishii Itsuko
  • Journal Title: Therapeutic Drug Monitoring Volume: - Issue: 3 Pages: 1-1
  • DOI: 10.1097/ftd.0000000000000721
  • Peer Reviewed
• [Presentation] Toward clinical implementation of UGT1A4 activity-based approach for the prediction of lamotrigine clearance. (2019)
  • Author(s): Masachika Fujiyoshi
  • Organizer: APSTJ Global Education Seminar 2019-1st
  • Invited
• [Presentation] 妊娠・授乳期におけるラモトリギンのクリアランスおよび乳汁移行性の変動 (2019)
  • Author(s): 岡田蛍子、藤吉正哉、土屋晃三、内田雅士、鈴木貴明、石井伊都子
  • Organizer: 日本薬学会第139年会
• [Remarks] 岡山大学薬学部 疾患薬理制御科学分野ホームページ
  • URL: http://www.pharm.okayama-u.ac.jp/lab/pmaphs/
• [Remarks] 岡山大学薬学部疾患薬理制御科学分野ホームページ
  • URL: http://www.pharm.okayama-u.ac.jp/lab/pmaphs/