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.
OBJECTIVE
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.
Clinical Development Center, Taiho Pharmaceutical Co., Ltd., 1-2-4, Uchikanda, Chiyoda-ku, Tokyo, 101-0047, Japan, ka-saito@taiho.co.jp.
Kaku
K
Saito
Hirotaka
H
Nagashima
Kazuharu
K
Noguchi
Kunihiro
K
Yoshisue
Tatsushi
T
Yokogawa
Eiji
E
Matsushima
Takeshi
T
Tahara
Shigeru
S
Takagi
D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects* / Q000493:pharmacokinetics; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D011755:Pyrophosphatases / Q000037:antagonists & inhibitors*; D055815:Young Adult
D011755:Pyrophosphatases; C023278:uridine triphosphatase; D005472:Fluorouracil