Abstract B90: First-in-human, phase I dose-escalation study of the pharmacokinetics and safety of single and multiple doses of a first-in-class enhancer of fluoropyrimidines, dUTPase inhibitor (TAS-114) in healthy male volunteers.
Authors: Saito Kaku , Nagashima Hirotaka , Noguchi Kazuharu , Yoshisue Kunihiro , Yokogawa Tatsushi , Matsushima Eiji , Tahara Takeshi , Takagi Shigeru , Utsugi Teruhiro 
Published: August 2014

Background: Deoxyuridine triphosphatase (dUTPase) is a gatekeeper enzyme for uracil misincorporation and is considered to be an important factor for resistance to 5-Fluorouracil. TAS-114 is a first-in class oral dUTPase inhibitor, which acts as a modulator of the pyrimidine nucleotide metabolic pathway. Animal toxicology studies revealed no significant adverse events. This was a first-in-human study that investigated the pharmacokinetics (PK) and safety of single agent TAS-114 when given at single and multiple doses in healthy male volunteers.

Materials and Methods: This was a single center, Phase 1, double-blind, placebo-controlled, randomized parallel study. For the single-dose cohort, subjects received a single dose of TAS-114 at 6, 18, 60, 150, and 300 mg in a fasting condition. The magnitude of dihydropyrimidine dehydrogenase (DPD) inhibition and the food effect on TAS-114 PK were also investigated. For the multiple-dose cohort, subjects received TAS-114 twice daily on days 1 to 14 consecutively, and then once on day 22 to investigate the auto-induction potential of CYP3A4 and its recovery during the rest period.

Results: The study enrolled 25 subjects in the dose-escalating single-dose cohort and 10 subjects in the multiple-dose cohort. PK parameters in the single-dose cohort are shown in the Table. The disposition of TAS-114 followed linear kinetics. The elimination half-life was approximately 2 hours. There was no significant food effect on the TAS-114 AUC. 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 significant changes in TAS-114 exposure or in urinary 6β hydroxycortisol/cortisol ratio (parameter for the induction of CYP3A4) were observed after repeated doses. No notable safety concerns at these dose levels were reported.

Conclusion: TAS-114 has shown both a favorable safety and pharmacokinetic profile after single and repeated doses. Global phase 1 programs of TAS-114 in combination with capecitabine or S-1 are underway.

Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B90.

Citation Format: Kaku Saito, Hirotaka Nagashima, Kazuharu Noguchi, Kunihiro Yoshisue, Tatsushi Yokogawa, Eiji Matsushima, Takeshi Tahara, Shigeru Takagi, Teruhiro Utsugi. First-in-human, phase I dose-escalation study of the pharmacokinetics and safety of single and multiple doses of a first-in-class enhancer of fluoropyrimidines, dUTPase inhibitor (TAS-114) in healthy male volunteers. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B90.