Pharmacokinetics and clinical effectiveness of new antiepileptic drugs in patients with refractory epilepsy

• Project/Area Number: 26860123
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Medical pharmacy
• Research Institution: National Epilepsy Center, Shizuoka Institute of Epilepsy and Neurological Disorders
• Principal Investigator: Yamamoto Yoshiaki 独立行政法人国立病院機構(静岡・てんかん神経医療センター臨床研究部), その他部局等, その他 (60596245)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000); Fiscal Year 2016: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000); Fiscal Year 2015: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2014: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
• Keywords: てんかん / 薬物相互作用 / 血中濃度モニタリング / 臨床 / 新規抗てんかん薬

Outline of Final Research Achievements

This study identified factors affecting the pharmacokinetics of new antiepileptic drugs (AEDs) and evaluated the therapeutic concentration range of AEDs. We analyzed 1,653 plasma concentrations of lamotrigine and 1,217 plasma concentrations of topiramate. The concentration to dose ratio as the plasma concentration divided by the weight-adjusted dose was used as a pharmacokinetic parameter. Concomitant use of hepatic enzyme inducers (phenytoin, phenobarbital, and carbamazepine) markedly reduced the plasma concentrations and can could impair decrease its antiepileptic effect.

Research Products

• [Journal Article] Therapeutic drug monitoring for perampanel in Japanese epilepsy patients: Influence of concomitant antiepileptic drugs (2017)
  • Author(s): Yamamoto Y, Usui N, Nishida T, Takahashi Y, Imai K, Kagawa Y, Inoue Y
  • Journal Title: Ther Drug Monit Volume: 印刷中
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Effect of CYP Inducers/Inhibitors on Topiramate Concentration: Clinical Value of Therapeutic Drug Monitoring. (2017)
  • Author(s): Yamamoto Y, Takahashi Y, Imai K, Kagawa Y, Inoue Y
  • Journal Title: Ther Drug Monit Volume: 39 Issue: 1 Pages: 55-61
  • DOI: 10.1097/ftd.0000000000000367
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Add-on stiripentol elevates serum valproate levels in patients with or without concomitant topiramate therapy (2017)
  • Author(s): Jogamoto T, Yamamoto Y, Fukuda M, Suzuki Y, Imai K, Takahashi Y, Inoue Y, Ohtsuka Y
  • Journal Title: Epilepsy Res Volume: 130 Pages: 7-12
  • DOI: 10.1016/j.eplepsyres.2016.12.014
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] 病気とくすり (2017)
  • Author(s): 山本吉章
  • Journal Title: 薬局 Volume: 68 Pages: 685-694
• [Journal Article] Evidence Update 2017 抗てんかん薬 (2017)
  • Author(s): 山本吉章
  • Journal Title: 薬局 Volume: 68 Pages: 74-77
• [Journal Article] Factors that influence the pharmacokinetics of lamotrigine in Japanese patients with epilepsy (2016)
  • Author(s): Inoue K, Yamamoto Y, Suzuki E, Takahashi T, Umemura A, Takahashi Y, Imai K, Inoue Y, Hirai K, Tsuji D, Itoh K
  • Journal Title: Eur J Clin Pharmacol. Volume: 72 Issue: 5 Pages: 555-562
  • DOI: 10.1007/s00228-016-2008-2
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] 難治てんかん患者を対象とした抗てんかん薬の薬物相互作用解析：酵素誘導能を有する抗てんかん薬が与える影響 (2016)
  • Author(s): 山本吉章
  • Journal Title: 医療薬学 Volume: 42 Pages: 389-399
  • NAID: 130005696936
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] 治療域が狭い・副作用が出やすい薬剤におけるDDIマネジメントの実践例 抗てんかん薬 (2016)
  • Author(s): 山本吉章
  • Journal Title: 薬局 Volume: 67 Pages: 2556-2559
• [Journal Article] Factors that influence the pharmacokinetics of lamotrigine in Japanese patients with epilepsy (2016)
  • Author(s): Inoue K, Yamamoto Y, Suzuki E, Takahashi T, Umemura A, Takahashi Y, Imai K, Inoue Y, Hirai K, Tsuji D, Itoh K.
  • Journal Title: Eur J Clin Pharmacol Volume: in press
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Influence of glutamine synthetase gene polymorphisms on the development of hyperammonemia during valproic acid-based therapy. (2015)
  • Author(s): Inoue K, Takahashi T, Yamamoto Y, Suzuki E, Takahashi Y, Imai K, Inoue Y, Hirai K, Tsuji D, Itoh K.
  • Journal Title: Seizure Volume: 33 Pages: 76-80
  • DOI: 10.1016/j.seizure.2015.10.015
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Changing incidence of hyperammonemia in Japan from 2006 to 2013: expansion of new antiepileptic drugs reduces the risk of hyperammonemia. (2015)
  • Author(s): Yamamoto Y, Takahashi Y, Imai K, Mishima N, Kagawa Y, Inoue Y.
  • Journal Title: Eur J Clin Pharmacol. Volume: 71 Issue: 12 Pages: 1517-1524
  • DOI: 10.1007/s00228-015-1939-3
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Determination of stiripentol in plasma by high-performance liquid chromatography with fluorescence detection (2015)
  • Author(s): Takahashi R, Imai K, Yamamoto Y, Takahashi Y, Hamano S, Yoshida H
  • Journal Title: Jpn. J. Pharm. Health Care Sci. Volume: 41 Pages: 643-650
  • NAID: 130006855776
  • Peer Reviewed / Open Access
• [Journal Article] Influence of uridine diphosphate glucuronosyltransferase inducers and inhibitors on the plasma lamotrigine concentration in pediatric patients with refractory epilepsy. (2015)
  • Author(s): Yamamoto Y, Takahashi Y, Imai K, Takahashi M, Nakai M, Inoue Y, Kagawa Y.
  • Journal Title: Drug Metab Pharmacokinet Volume: 30 Issue: 3 Pages: 214-220
  • DOI: 10.1016/j.dmpk.2015.01.001
  • NAID: 50014429953
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Individualized Phenytoin Therapy for Japanese Pediatric Patients With Epilepsy Based on CYP2C9 and CYP2C19 Genotypes. (2015)
  • Author(s): Yamamoto Y, Takahashi Y, Imai K, Miyakawa K, Ikeda H, Ueda Y, Yamaguchi T, Nasu H, Ohtani H, Shigematsu H, Kagawa Y, Inoue Y.
  • Journal Title: Ther Drug Monit. Volume: 37 Issue: 2 Pages: 229-235
  • DOI: 10.1097/ftd.0000000000000128
  • Peer Reviewed
• [Journal Article] Impact of cytochrome P450 inducers with or without inhibitors on the serum clobazam level in patients with antiepileptic polypharmacy (2014)
  • Author(s): Yamamoto Y, Takahashi Y, Imai K, Takahashi M, Nakai M, Inoue Y, Kagawa Y.
  • Journal Title: Eur J Clin Pharmacol. Volume: 70 Issue: 10 Pages: 1203-1210
  • DOI: 10.1007/s00228-014-1719-5
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] 4217C>A polymorphism in carbamoyl-phosphate synthase 1 gene may not associate with hyperammonemia development during valproic acid-based therapy. (2014)
  • Author(s): Inoue K, Suzuki E, Takahashi T, Yamamoto Y, Yazawa R, Takahashi Y, Imai K, Miyakawa K, Inoue Y, Tsuji D, Hayashi H, Itoh K.
  • Journal Title: Epilepsy Res. Volume: 108 Issue: 6 Pages: 1046-1051
  • DOI: 10.1016/j.eplepsyres.2014.04.008
  • Peer Reviewed
• [Journal Article] Interaction between sulthiame and clobazam: Sulthiame inhibits the metabolism of clobazam, possibly via an action on CYP2C19. (2014)
  • Author(s): Yoshiaki Yamamoto, Yukitoshi Takahashi, Katsumi Imai, Yukiko Mogami, Kazumi Matsuda, Masahiko Nakai, Yoshiyuki Kagawab, Yushi Inoue
  • Journal Title: Epilepsy & Behavior Volume: 34 Pages: 124-126
  • DOI: 10.1016/j.yebeh.2014.03.018
  • Peer Reviewed
• [Journal Article] Influence of uridine diphosphate glucuronosyltransferase 2B7 -161C>T polymorphism on the concentration of valproic acid in pediatric epilepsy patients. (2014)
  • Author(s): Inoue K, Suzuki E, Yazawa R, Yamamoto Y, Takahashi T, Takahashi Y, Imai K, Koyama S, Inoue Y, Tsuji D, Hayashi H, Itoh K.
  • Journal Title: Ther Drug Monit. Volume: 36 Issue: 3 Pages: 406-409
  • DOI: 10.1097/ftd.0000000000000012
  • Peer Reviewed
• [Journal Article] エキスパートに学ぶ 薬物治療管理の実践ポイント てんかんにおける相互作用のチェックポイント (2014)
  • Author(s): 山本吉章
  • Journal Title: 薬局 Volume: 65 Pages: 108-113
• [Presentation] Inhibitory effect of stiripentol on pharmacokinetics of clobazam in patients with Dravet syndrome (2016)
  • Author(s): Yamamoto Y, Takahashi Y, Imai K, Kagawa Y, Inoue Y
  • Organizer: 70th American Epirepsy Scoiety Annual Meeting
  • Place of Presentation: Houston
  • Year and Date: 2016-12-02
  • Int'l Joint Research
• [Presentation] Therapeutic monitoring for topiramate in patients with refractory epilepsy (2016)
  • Author(s): Yamamoto Y, Takahashi Y, Imai K, Kagawa Y, Inoue Y
  • Organizer: 第50回日本てんかん学会学術集会
  • Place of Presentation: 静岡
  • Year and Date: 2016-10-07
• [Presentation] スチリペントールの薬物動態と注意すべき相互作用 (2016)
  • Author(s): 山本吉章
  • Organizer: 第50回日本てんかん学会学術集会
  • Place of Presentation: 静岡
  • Year and Date: 2016-10-07
  • Invited
• [Presentation] 臨床で問題となる抗てんかん薬の相互作用 (2016)
  • Author(s): 山本吉章
  • Organizer: 第24回医療薬学フォーラム
  • Place of Presentation: 大津
  • Year and Date: 2016-06-25
  • Invited
• [Presentation] Use of antiepileptic drugs and risk of dyslipidemia: a large-scale cross-sectional study (2016)
  • Author(s): Yamamoto Y, Takahashi Y, Terada K, Imai K, Kagawa Y, Inoue Y
  • Organizer: 11th Asia Oceania Epilepsy Congress
  • Place of Presentation: Hong Kong
  • Year and Date: 2016-05-13
  • Int'l Joint Research
• [Presentation] Use of antiepileptic drugs and risk of dyslipidemia: a large-scale cross-sectional study (2016)
  • Author(s): Yamamoto Y, Terada K, Takahashi Y, Imai K, Kagawa Y, Inoue Y
  • Organizer: The 11th Asian & Oceanian Epilepsy Congress
  • Place of Presentation: Hong Kong
  • Year and Date: 2016-05-13
  • Int'l Joint Research
• [Presentation] 奨励賞受賞講演 難治てんかん患者を対象とした抗てんかん薬の薬物相互作用解析 (2015)
  • Author(s): 山本吉章
  • Organizer: 日本医療薬学会25年会
  • Place of Presentation: 横浜
  • Year and Date: 2015-11-21
• [Presentation] Interactions of stiripentol with valproate in patients with Dravet syndrome. (2015)
  • Author(s): Toshihiro Jogamoto, Yoshiaki Yamamoto, Mitsumasa Fukuda, Yuka Suzuki, Katsumi Imai, Yukitoshi Takahashi, Yushi Inoue, Yoko Ohtsuka.
  • Organizer: The 49th Congress of the Japan Epilepsy Society
  • Place of Presentation: Nagasaki
  • Year and Date: 2015-10-29
• [Presentation] てんかん患者の脂質代謝異常発症に寄与する抗てんかん薬の検討 (2015)
  • Author(s): 山本吉章、寺田清人, 今井克美, 高橋幸利, 賀川義之, 井上有史
  • Organizer: 第49回日本てんかん学会学術集会
  • Place of Presentation: 長崎
  • Year and Date: 2015-10-29
• [Presentation] Therapeutic drug monitoring for lamotrigine in pediatric epilepsy patients (2015)
  • Author(s): Yamamoto Y, Takahashi Y, Imai1 K, Y. Inoue Y, Kagawa Y.
  • Organizer: The 12th European Association for Clinical Pharmacology and Therapeutics Congress
  • Place of Presentation: Madrid, Spain
  • Year and Date: 2015-06-27 – 2015-06-30
• [Presentation] Therapeutic drug monitoring for lamotrigine in pediatric epilepsy patients (2015)
  • Author(s): Yoshiaki Yamamoto, Yukitoshi Takahashi, Katsumi Imai, Yushi Inoue, Yoshiyuki Kagawa
  • Organizer: 12th Congress of the European Association for Clinical Pharmacology and Therapeutics
  • Place of Presentation: Madrid
  • Year and Date: 2015-06-27
  • Int'l Joint Research
• [Presentation] 新規抗てんかん薬の血中濃度モニタリング (2015)
  • Author(s): 山本吉章
  • Organizer: 第32回日本TDM学会・学術大会
  • Place of Presentation: 松本
  • Year and Date: 2015-05-23
• [Presentation] バルプロ酸による高アンモニア血症の発生率の年次推移 (2015)
  • Author(s): 山本吉章、高橋幸利、今井克美、井上有史、賀川義之
  • Organizer: 日本薬学会第回135年会
  • Place of Presentation: 神戸
  • Year and Date: 2015-03-25 – 2015-03-28
• [Presentation] Pharmacokinetics of Stiripentol (2014)
  • Author(s): 山本吉章
  • Organizer: 第49回日本てんかん学会
  • Place of Presentation: 東京
  • Year and Date: 2014-10-01 – 2014-10-03
• [Presentation] 小児てんかん患者を対象としたラモトリギンの相互作用解析 (2014)
  • Author(s): 山本吉章、中井正彦、高橋昌明、今井克美、高橋幸利、賀川義之
  • Organizer: 第24回日本医療薬学会年会
  • Place of Presentation: 名古屋
  • Year and Date: 2014-09-27 – 2014-09-28
• [Presentation] バルプロ酸による高アンモニア血症発症と遺伝子多型の関連性、第24回 (2014)
  • Author(s): 高橋 俊樹、井上 和幸、鈴木 絵莉、山本 吉章、高橋 幸利、今井 克美、宮川 絋、井上 有史、辻 大樹、伊藤 邦彦
  • Organizer: 第24回日本医療薬学会年会
  • Place of Presentation: 名古屋
  • Year and Date: 2014-09-27 – 2014-09-28
• [Presentation] Stiripentolの遊離血中濃度と併用薬剤やCYP2C19変異等との関連の検討 (2014)
  • Author(s): 那須裕郷、高橋幸利、高橋良平、山本吉章、吉冨晋作、渡邉陽和、山口解冬、大谷英之、池田浩子、今井克美、重松秀夫、井上有史
  • Organizer: 第56回日本小児神経学会
  • Place of Presentation: 浜松
  • Year and Date: 2014-05-29 – 2014-05-31