1 3Cancer Chemother Pharmacol (2014) 73:577–583DOI 10.1007/s00280-014-2383-2ORIGINAL ARTICLEFirst?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 volunteersKaku Saito · Hirotaka Nagashima · Kazuharu Noguchi · Kunihiro Yoshisue · Tatsushi Yokogawa · Eiji Matsushima · Takeshi Tahara · Shigeru Takagi Received: 2 August 2013 / Accepted: 9 January 2014 / Published online: 23 January 2014 © Springer-Verlag Berlin Heidelberg 2014or higher of TAS-114, suggesting that significant inhibi-tion 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 stud-ies of the combination chemotherapies in cancer patients and may reduce the safety risk in the frail cancer patients.Keywords First-in-human study · dUTPase · 5-Fluorouracil · PK · Safety · DPD · CYP3A4Introduction5-Fluorouracil (5-FU), a tumor antimetabolite, was discov-ered by Heidelberger et al. [1] in 1957. Many combination chemotherapies employing 5-FU with chemical modulators such as leucovorin and other antimalignant tumor agents have demonstrated efficacy against a variety of carcinomas to date [2]. Chemotherapies using oral 5-FU such as capecit-abine or S-1 are shown to be effective but can cause intrinsic and acquired resistance. Therefore, the development of new drugs that can be expected to achieve higher efficacy than the existing fluoropyrimidines is urgently required.Thymidylate synthase (TS) is a primary target of 5-FU, and its inhibition by the covalent binding of 2′-deoxy-5-fluorouridine-5′-monophosphate (FdUMP) results in depletion of thymidine-5′-triphosphate (dTTP), termed as “thymineless death” [3–9]. Under the inhibition of TS, its substrate, 2′-deoxyuridine-5′-monophosphate (dUMP), and unbounded FdUMP are sequentially phosphorylated to Abstract Purpose TAS-114 is a first-in-class oral deoxyuridine triphosphatase (dUTPase) inhibitor, which acts as a modu-lator 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 dis-position of TAS-114 followed linear kinetics. The elimina-tion 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 K. Saito (*) · K. Noguchi · T. Tahara · S. Takagi Clinical Development Center, Taiho Pharmaceutical Co., Ltd., 1-2-4, Uchikanda, Chiyoda-ku, Tokyo 101-0047, Japane-mail: ka-saito@taiho.co.jpH. Nagashima Yanagibashi-Clinical Trial Center, Yanagibashi Hospital, Life Extension Research Institute Foundation, 2-20-4, Yanagibashi, Taito-ku, Tokyo 111-0052, JapanK. Yoshisue · T. Yokogawa Tsukuba Research Center, Taiho Pharmaceutical Co., Ltd., 3, Okubo, Tsukuba-shi, Ibaraki 300-2611, JapanE. Matsushima Tokushima Research Center, Taiho Pharmaceutical Co., Ltd., 224-2, Ebisuno, Hiraishi, Kawauchi-cho, Tokushima 771-0194, Japan
