First-in-human, phase I dose-escalation study of single and multiple doses of a first-in-class enhancer of fluoropyrimidines, a dUTPase inhibitor (TAS-114) in healthy male volunteers

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• 作者：Kaku Saito (1)
  Hirotaka Nagashima (2)
  Kazuharu Noguchi (1)
  Kunihiro Yoshisue (3)
  Tatsushi Yokogawa (3)
  Eiji Matsushima (4)
  Takeshi Tahara (1)
  Shigeru Takagi (1)
  
• 关键词：First ; in ; human study ; dUTPase ; 5 ; Fluorouracil ; PK ; Safety ; DPD ; CYP3A4
• 刊名：Cancer Chemotherapy and Pharmacology
• 出版年：2014
• 出版时间：March 2014
• 年：2014
• 卷：73
• 期：3
• 页码：577-583
• 全文大小：446 KB
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  6. Lenz HJ, Leichman CG, Danenberg KD, Danenberg PV, Groshen S, Cohen H et al (1996) Thymidylate synthase mRNA level in adenocarcinoma of the stomach: a predictor for primary tumor response and overall survival. J Clin Oncol 14:176-82
  7. Peters GJ, van der Wilt CL, van Groeningen CJ, Smid K, Meijer S, Pinedo HM (1994) Thymidylate synthase inhibition after administration of fluorouracil with or without leucovorin in colon cancer patients: implications for treatment with fluorouracil. J Clin Oncol 12:2035-042
  8. Aschele C, Debernardis D, Casazza S, Antonelli G, Tunesi G, Baldo C et al (1999) Immunohistochemical quantitation of thymidylate synthase expression in colorectal cancer metastases predicts for clinical outcome to fluorouracil-based chemotherapy. J Clin Oncol 17:1760-770
  9. Ichikawa W, Takahashi T, Suto K, Yamashita T, Nihei Z, Shirota Y et al (2004) Thymidylate synthase predictive power is overcome by irinotecan combination therapy with S-1 for gastric cancer. Br J Cancer 91:1245-250 CrossRef
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  11. Koehler SE, Ladner RD (2004) Small interfering RNA-mediated suppression of dUTPase sensitizes cancer cell lines to thymidylate synthase inhibition. Mol Pharmacol 66:620-26
  12. Ladner RD, Lynch FJ, Groshen S, Xiong YP, Sherrod A, Caradonna SJ et al (2000) dUTP nucleotidohydrolase isoform expression in normal and neoplastic tissues: association with survival and response to 5-fluorouracil in colorectal cancer. Cancer Res 60:3493-503
  13. Adlard JW, Richman SD, Royston P, Allan JM, Meade A, Parmar M et al (2004). Assessment of multiple markers for association with response rate (RR) and failure-free survival (FFS) in patients with advanced colorectal cancer (CRC) treated with chemotherapy in the MRC CR08 (FOCUS) randomized trial. J Clin Oncol ASCO Annual meeting proceedings (post-meeting edition). Vol 22: Abstract no. 9506
  14. Richman S, Braun MS, Adlard JW, Daly C, Turner F, Barrett J et al (2006) Prognostic value of thymidylate synthase (TS) expression on failure-free survival of fluorouracil-treated metastatic colorectal cancer patients. J Clin Oncol ASCO Annual meeting proceedings part I. Vol 24 (June 20 Supplement): Abstract no. 10011
  15. Nobili S, Napoli C, Landini I, Morganti M, Cianchi F, Valanzano R et al (2011) Identification of potential pharmacogenomic markers of clinical efficacy of 5-fluorouracil in colorectal cancer. Int J Cancer 128:1935-945 CrossRef
  16. Yano W, Yokogawa T, Fukuoka M, Miyakoshi H, Miyahara S, Ueno H et al (2012) In vitro characterization of a novel dUTPase inhibitor, TAS-114, as a fluoropyrimidine enhancer. Eur J Cancer 48(Suppl 6):22 CrossRef
  17. Yokogawa T, Wakasa T, Yano W, Yoshisue K, Fujioka A, Eshima K et al (2012) TAS-114 enhances S-1 activity in vivo when used in combination. Eur J Cancer 48(Suppl 6):22 CrossRef
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• 作者单位：Kaku Saito (1)
  Hirotaka Nagashima (2)
  Kazuharu Noguchi (1)
  Kunihiro Yoshisue (3)
  Tatsushi Yokogawa (3)
  Eiji Matsushima (4)
  Takeshi Tahara (1)
  Shigeru Takagi (1)
  
  1. Clinical Development Center, Taiho Pharmaceutical Co., Ltd., 1-2-4, Uchikanda, Chiyoda-ku, Tokyo, 101-0047, Japan
  2. Yanagibashi-Clinical Trial Center, Yanagibashi Hospital, Life Extension Research Institute Foundation, 2-20-4, Yanagibashi, Taito-ku, Tokyo, 111-0052, Japan
  3. Tsukuba Research Center, Taiho Pharmaceutical Co., Ltd., 3, Okubo, Tsukuba-shi, Ibaraki, 300-2611, Japan
  4. Tokushima Research Center, Taiho Pharmaceutical Co., Ltd., 224-2, Ebisuno, Hiraishi, Kawauchi-cho, Tokushima, 771-0194, Japan
  
• ISSN：1432-0843

文摘

Purpose TAS-114 is a first-in-class oral deoxyuridine triphosphatase (dUTPase) inhibitor, which acts as a modulator of the pyrimidine nucleotide metabolic pathway. This was a first-in-human, phase 1 study that investigated the pharmacokinetics (PK) and safety of single-agent TAS-114 when it was given at single and multiple doses. Methods For the single-dose cohort (n?=?25), healthy male volunteers received a single dose of TAS-114 at 6, 18, 60, 150, and 300?mg. The magnitude of dihydropyrimidine dehydrogenase (DPD) inhibition and the food effect on TAS-114 PK were also investigated. For the multiple-dose cohort (n?=?10), subjects received TAS-114 for 14?days consecutively. Results In the dose-escalating single-dose cohort, the disposition of TAS-114 followed linear kinetics. The elimination half-life was approximately 2?h. The urine excretion rate and food effect were minimal. A significant increase in uracil Cmax was observed at administered doses of 150?mg or higher of TAS-114, suggesting that significant inhibition of DPD occurred at these doses. No apparent CYP3A4 auto-induction was observed in the multiple-dose cohort. No significant safety concerns at these dose levels were noted after single and multiple dosing. Conclusions TAS-114 has shown both a favorable safety and pharmacokinetic profile after single and repeated doses. TAS-114 was considered to possess a moderate DPD inhibitory effect. These findings will facilitate clinical studies of the combination chemotherapies in cancer patients and may reduce the safety risk in the frail cancer patients.