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

Cancer Chemother Pharmacol. 2014 Mar;73(3):577-83. doi: 10.1007/s00280-014-2383-2. Epub 2014 Jan 23.


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.

Publication types

  • Clinical Trial, Phase I
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Antineoplastic Combined Chemotherapy Protocols / administration & dosage*
  • Antineoplastic Combined Chemotherapy Protocols / adverse effects*
  • Antineoplastic Combined Chemotherapy Protocols / pharmacokinetics
  • Cohort Studies
  • Dose-Response Relationship, Drug
  • Double-Blind Method
  • Drug Administration Schedule
  • Fluorouracil / administration & dosage
  • Fluorouracil / adverse effects
  • Fluorouracil / pharmacokinetics
  • Healthy Volunteers
  • Humans
  • Male
  • Pyrophosphatases / antagonists & inhibitors*
  • Young Adult


  • Pyrophosphatases
  • uridine triphosphatase
  • Fluorouracil