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

• Published in: Cancer chemotherapy and pharmacology Vol. 73; no. 3; pp. 577 - 583
• Main Authors: Saito, Kaku, Nagashima, Hirotaka, Noguchi, Kazuharu, Yoshisue, Kunihiro, Yokogawa, Tatsushi, Matsushima, Eiji, Tahara, Takeshi, Takagi, Shigeru
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.03.2014; Springer; Springer Nature B.V
• Subjects: Adult; Antineoplastic agents; Antineoplastic Combined Chemotherapy Protocols - administration & dosage; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Antineoplastic Combined Chemotherapy Protocols - pharmacokinetics; Biological and medical sciences; Cancer Research; Cohort Studies; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Fluorouracil - administration & dosage; Fluorouracil - adverse effects; Fluorouracil - pharmacokinetics; Healthy Volunteers; Humans; Male; Medical sciences; Medicine; Medicine & Public Health; Oncology; Original Article; Pharmacology. Drug treatments; Pharmacology/Toxicology; Pyrophosphatases - antagonists & inhibitors; Young Adult; 5-Fluorouracil; dUTPase; First-in-human study; DPD; PK; Safety; CYP3A4; Antineoplastic agent; Cytochrome CYP3A4; Dose escalation; Isozyme; Toxicity; Multiple dose; pK; Fluorouracil; Human; Healthy subject; Enzyme; Transferases; Cytochrome P450; Fluoropyrimidine derivatives; Single dose; Enzyme inhibitor; ); Dihydropyrimidine dehydrogenase (NADP; Thymidylate synthase; dUTP pyrophosphatase; Antimetabolic; Methyltransferases; Phase I trial; Pyrimidine derivatives; Hydrolases; Oxidoreductases
• DOI: 10.1007/s00280-014-2383-2
• ISSN: 0344-5704; 1432-0843

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 C max 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.