Do patients taking tacrolimus need to undergo CYP3A5 genotyping along with blood concentration monitoring?

• Project/Area Number: 26460189
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Medical pharmacy
• Research Institution: Akita University
• Principal Investigator: Niioka Takenori 秋田大学, 医学部, 講師 (20722276)
• Co-Investigator(Renkei-kenkyūsha): MIURA Masatomo 秋田大学, 医学部, 教授 (30265194) ; SATOH Shigeru 秋田大学, 医学部, 教授 (80187195) ; TAKAHASHI Naoto 秋田大学, 医学部, 教授 (80344753)
• Research Collaborator: KAGAYA Hideaki 秋田大学, 病院, 主任
• Project Period (FY): 2014-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2015: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2014: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: タクロリムス / CYP3A5遺伝子多型 / 薬物動態 / 腎移植 / 骨髄移植 / TDM / エベロリムス / イトラコナゾール / 薬物動態学的相互作用 / 膠原病

Outline of Final Research Achievements

Appropriate tacrolimus (FK) treatment requires higher doses in CYP3A5 expressors (CYP3A5*1/*1 + *1/*3) compared with CYP3A5 nonexpressors (CYP3A5*3/*3), with the former also demonstrating longer times to achieve target trough concentration levels. On the other hand, the concentration of FK in the blood increases significantly in CYP3A5 nonexpressors taking CYP3A inhibitors, such as triazole antifungal agents. Therefore, FK administration should be dose-adjusted based on CYP3A5 genotype prior to initial FK administration, or co-administered with a CYP3A5 inhibitor. Thus, information on the CYP3A5 genotype is useful for therapeutic drug monitoring of FK.

Research Products

• [Journal Article] Prediction of Tacrolimus Exposure by CYP3A5 Genotype and Exposure of Co-Administered Everolimus in Japanese Renal Transplant Recipients. (2018)
  • Author(s): Kagaya H, Niioka T, Saito M, Inoue T, Numakura K, Yamamoto R, Akamine Y, Habuchi T, Satoh S, Miura M.
  • Journal Title: Int J Mol Sci Volume: 19 Issue: 3 Pages: 882-882
  • DOI: 10.3390/ijms19030882
  • NAID: 120007172094
  • Peer Reviewed / Open Access
• [Journal Article] Impact of the CYP3A5 genotype on the distributions of dose-adjusted trough concentrations and incidence of rejection in Japanese renal transplant recipients receiving different tacrolimus formulations. (2017)
  • Author(s): Niioka T, Kagaya H, Saito M, Inoue T, Numakura K, Yamamoto R, Habuchi T, Satoh.
  • Journal Title: Clin Exp Nephrol. Volume: 印刷中 Issue: 5 Pages: 787-796
  • DOI: 10.1007/s10157-016-1375-4
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Influence of everolimus on the pharmacokinetics of tacrolimus in Japanese renal transplant patients. (2016)
  • Author(s): Niioka T, Kagaya H, Saito M, Inoue T, Numakura K, Yamamoto R, Akamine Y, Habuchi T, Satoh S, Miura M.
  • Journal Title: Int J Urol. Volume: in press Issue: 6 Pages: 484-490
  • DOI: 10.1111/iju.13081
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Effect of CYP3A5 and ABCB1 polymorphisms on the interaction between tacrolimus and itraconazole in patients with connective tissue disease. (2015)
  • Author(s): Togashi M, Niioka T, Komatsuda A, Nara M, Okuyama S, Omokawa A, Abumiya M, Wakui H, Takahashi N, Miura M.
  • Journal Title: Eur J Clin Pharmacol. Volume: 71 Issue: 9 Pages: 1091-7
  • DOI: 10.1007/s00228-015-1901-4
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Effects of CYP3A5 polymorphism and the tacrolimus 12?h concentration on tacrolimus-induced acute renal dysfunction in patients with lupus nephritis. (2015)
  • Author(s): Niioka T, Komatsuda A, Kato S, Togashi M, Okuyama S, Omokawa A, Nara M, Wakui H, Takahashi N, Miura M.
  • Journal Title: Xenobiotica. Volume: 45 Pages: 1147-53
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Capability of utilizing CYP3A5 polymorphisms to predict therapeutic dosage of tacrolimus at early stage post-renal transplantation. (2015)
  • Author(s): Niioka T, Kagaya H, Saito M, Inoue T, Numakura K, Habuchi T, Satoh S, Miura M.
  • Journal Title: Int J Mol Sci. Volume: 16 Issue: 1 Pages: 1840-1854
  • DOI: 10.3390/ijms16011840
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] 腎移植患者におけるタクロリムス体内曝露量の個体間変動に及ぼすCYP3A5遺伝子多型およびエベロリムスの影響 (2017)
  • Author(s): 加賀谷 英彰、新岡 丈典、齋藤 満、井上 高光、沼倉 一幸、羽渕 友則、佐藤 滋、三浦 昌朋
  • Organizer: 医療薬学会
• [Presentation] 遺伝子多型情報を用いた抗がん剤と免疫抑制剤の個別化投与設計 (2016)
  • Author(s): 新岡丈典，三浦昌朋
  • Organizer: 日本薬物動態学会第31回年会
  • Place of Presentation: 松本
  • Year and Date: 2016-10-13
  • Invited
• [Presentation] 遺伝子多型に基づく免疫抑制薬投与計画の個別化へのアプローチ (2016)
  • Author(s): 新岡丈典
  • Organizer: 第52回日本移植学会総会
  • Place of Presentation: 東京
  • Year and Date: 2016-09-29
  • Invited
• [Presentation] 血液がん領域におけるTDMの実践と個別化療法への応用 (2016)
  • Author(s): 新岡丈典
  • Organizer: 日本TDM学会第49回セミナー
  • Place of Presentation: 仙台
  • Year and Date: 2016-09-03
  • Invited
• [Presentation] タクロリムス個別化投与設計においてCYP3A5遺伝子多型情報を有効利用するために (2016)
  • Author(s): 新岡丈典
  • Organizer: 日本病院薬剤師会東北ブロック第6回学術大会
  • Place of Presentation: 郡山
  • Year and Date: 2016-05-21
  • Invited
• [Presentation] 膠原病患者におけるタクロリムスとイトラコナゾールとの薬物相互作用に及ぼすCYP3A5およびABCB1遺伝子多型の影響 (2015)
  • Author(s): 新岡丈典, 富樫賢, 小松田敦, 奈良瑞穂, 奥山慎, 面川歩, 鐙屋舞子, 涌井秀樹, 高橋直人, 三浦昌朋
  • Organizer: 日本医療薬学会第25回年会
  • Place of Presentation: 横浜
  • Year and Date: 2015-11-21
• [Presentation] 臨床濃度範囲でエベロリムスはタクロリムス体内動態に影響しない (2015)
  • Author(s): 新岡丈典, 加賀谷英彰, 齋藤満, 井上高光, 沼倉一幸, 羽渕友則, 佐藤滋, 三浦昌朋
  • Organizer: 第51回日本移植学会総会
  • Place of Presentation: 熊本
  • Year and Date: 2015-10-01
• [Presentation] Influence of CYP3A5 gene polymorphisms on pharmacokinetics of tacrolimus modified-release once-daily after hematopoietic stem cell transplantation. (2015)
  • Author(s): Takaya Yamashita, Naohito Fujishima, Masatomo Miura, Takenori Niioka, Maiko Abumiya, Kazuaki Teshima, Kumi Ubukawa, Miho Nara, Masumi Fujishima, Yoshihiro Kameoka, Makoto Hirokawa, Naoto Takahashi
  • Organizer: 20th Congress of European Hematology Association
  • Place of Presentation: Vienna
  • Year and Date: 2015-06-11
  • Int'l Joint Research
• [Presentation] ループス腎炎患者の急性腎障害発症に及ぼすタクロリムスの血中濃度とCYP3A5遺伝子多型の影響 (2015)
  • Author(s): 富樫賢, 新岡丈典, 奈良瑞穂, 面川歩, 奥山慎, 加藤正太郎, 涌井秀樹, 三浦昌朋, 小松田敦
  • Organizer: 第58回日本腎臓学会学術総会
  • Place of Presentation: 名古屋
  • Year and Date: 2015-06-05
• [Presentation] タクロリムスTDMにおけるCYP3A5遺伝子多型解析の有用性と経済的効果 (2015)
  • Author(s): 新岡 丈典
  • Organizer: 第32回日本TDM学会・学術大会
  • Place of Presentation: 松本
  • Year and Date: 2015-05-23
  • Invited
• [Presentation] タクロリムス至適投与量に対する決定要因の経時的検討 (2014)
  • Author(s): 新岡丈典、加賀谷英彰、齋藤満、井上高光、沼倉一幸、羽渕友則、佐藤滋、三浦昌朋
  • Organizer: 第50回日本移植学会総会
  • Place of Presentation: 京王プラザホテル(東京)
  • Year and Date: 2014-09-10 – 2014-09-12
• [Book] 月刊薬事 (2017)
  • Author(s): 新岡丈典
  • Total Pages: 5
  • Publisher: じほう
• [Remarks] 秋田大学医学部附属病院 薬剤部
  • URL: http://di.hos.akita-u.ac.jp/index.html
• [Remarks] 秋田大学医学部附属病院 薬剤部
  • URL: http://di.hos.akita-u.ac.jp/