Taiho Pharma United States Inc.

Princeton, NJ, United States

Taiho Pharma United States Inc.

Princeton, NJ, United States
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Scheulen M.E.,University of Duisburg - Essen | Saito K.,Taiho Pharma United States Inc. | Hilger R.A.,University of Duisburg - Essen | Mende B.,University of Duisburg - Essen | And 2 more authors.
Cancer Chemotherapy and Pharmacology | Year: 2012

Purpose: S-1 is a novel oral fluoropyrimidine comprised of FT and two modulators, gimeracil (CDHP) and oteracil potassium (Oxo). This study investigated the food effects on the pharmacokinetics (PK) of Oxo, other components of S-1, and their metabolites at different gastric pH adjusted by proton pump inhibitor (PPI). Methods: Patients with and without PPI were treated with S-1 at 30 mg/m 2 twice daily orally on days 1-7 under either fed or fasting condition, and then were crossed over to fasting/fed conditions on days 15-21 with washout on days 8-14 and 22-28. Results: The study enrolled 55 patients including 27 PK-evaluable patients. For the single-dose and multiple-dose pharmacokinetics, the administration of S-1 under fed conditions resulted in decreased exposure to Oxo relative to fasting administration. There was a marginal decrease in exposure to CDHP and 5-FU under fed versus fasting conditions, although FT exposure was not altered by food, which demonstrated lack of food effect. PPI administration together with S-1 did not significantly change its bioavailability. Conclusions: Oxo exposure was reduced under fed compared to fasting condition. To increase the bioavailability of S-1, the administration of S-1 under fasting condition was more effective in the western countries. © 2011 Springer-Verlag.


Buzdar A.,University of Houston | Vogel C.,Lynn Cancer Institute | Schwartzberg L.,Medical Oncology | Garin A.,Russian Cancer Research Center | And 5 more authors.
Cancer | Year: 2012

BACKGROUND: The objective of this study was to evaluate 3 different doses of (7α)-21-(4-[(diethylamino)methyl]-2 methoxyphenoxy)-7 methyl-19 norpregna-1,3,5(10)-trien-3-ol 2-hydroxy-1,2,3-propanetricarboxylate (TAS-108) in patients with recurrent, hormone-responsive breast cancer. METHODS: In this randomized, double-blind, multicenter study, TAS-108 was administered daily at a dose of 40 mg, 80 mg, or 120 mg to postmenopausal patients with locally advanced, or inoperable, or metastatic hormone-receptor positive breast cancer. The primary efficacy outcome was clinical benefit (CB), defined as the total number of patients who achieved a complete response, a partial response, or stable disease for ≥24 weeks. The study was a 2-stage design in which 19 patients per dose group were planned in the first stage. If at least 3 patients in any dose group achieved a CB, then that dose group was to be allowed to continue enrolling for the second stage, and the group could include up to a total of 60 patients. RESULTS: The 40-mg and 80-mg groups met the criterion and enrolled patients into the second stage. In the 40-mg group, there were 13 CB events in 60 patients (21.7%); and, in the 80-mg group, there were 12 CB events in 60 patients (20%). The 120-mg daily dose was stopped early, because it failed to achieve the criterion. For the 40-mg and 80-mg groups, the median time to progression was 15.0 weeks and 15.9 weeks, respectively. Only 1 drug-related serious adverse event (grade 3 hyperglycemia) was reported. CONCLUSIONS: TAS-108 at 40 mg and 80 mg daily demonstrated clinical activity with an encouraging duration of benefit. Because of its superior safety profile, TAS-108 40 mg daily is recommended for further development. © 2011 American Cancer Society.


Govindan R.,University of Washington | Morgensztern D.,University of Washington | Kommor M.D.,Consulting in Blood Disorders and Cancer | Herbst R.S.,University of Texas M. D. Anderson Cancer Center | And 5 more authors.
Journal of Thoracic Oncology | Year: 2011

Purpose: Currently available agents for the treatment of advanced stage non-small cell lung cancer (NSCLC) have limited efficacy. S-1 is a novel formulation of oral fluoropyrimidine shown to be tolerable and active in patients with NSCLC in Japan. We conducted a multicenter phase II study in previously treated patients with NSCLC to evaluate the efficacy of single-agent S-1 in a predominantly non-Asian population. PATIENTS AND Methods: Patients with advanced NSCLC and previously treated with only one line of chemotherapy received oral S-1 at 30 mg/m every 12 hours for 14 consecutive days followed by a 7-day rest until meeting discontinuation criteria. The primary end point was to evaluate the overall response rate. Results: Fifty-seven patients were accrued from 21 centers across the United States. Overall response rates and stable disease according to independent review were 7.1% and 48.2%, respectively, with a disease control rate of 55.3%. Progression-free survival was 2.9 months, median overall survival 7.3 months, and 1-year survival 31.6%. There were no significant differences in survival according to histologic subtype. The treatment was well tolerated, with the most common treatment-related side effects being nausea (54%) and diarrhea (49%). Conclusion: Single-agent S-1 is well tolerated and has activity comparable with the other agents approved for use in recurrent/relapsed NSCLC. Copyright © 2011 by the International Association for the Study of Lung Cancer.


Saif M.W.,Columbia University | Rosen L.S.,Premiere Oncology | Saito K.,Taiho Pharma United States Inc. | Zergebel C.,Taiho Pharma United States Inc. | And 2 more authors.
Anticancer Research | Year: 2011

The purpose of this study was to investigate the effect of gimeracil (CDHP), a reversible dihydropyrimidine dehydrogenase (DPD) inhibitor, on the pharmacokinetics of 5-fluorouracil (5-FU) and other related metabolites by comparing the pharmacokinetic (PK) profile of S-1 (tegafur [FT] + CDHP + oteracil potassium [Oxo]) to that of FT alone. Patients and Methods: Patients with advanced solid tumors received single oral doses of S-1 (50 mg) and FT (800 mg) on days 1 and 8 in a randomized crossover fashion. Plasma samples were collected on days 1, 2, 3, 8, 9 and 10. Single-dose PK parameters were determined for FT, 5-FU and α-fluoro-β-alanine (FBAL). Following the single-dose crossover period, patients entered an extension phase and received treatment with S-1 b.i.d. for 14 days followed by a 7-day rest, repeated every 3 weeks. Results: A total of 12 patients were enrolled; median age was 59 years and mean body surface area was 1.94 m2. Following S-1 administration, 5-FU exposure was significantly greater (approximately 3-fold) compared to FT alone (p≤0.0007 for AUC0.inf, AUC0-last, and C max of 5-FU) despite the 16-fold higher dose of FT administered alone compared to S-1, while plasma concentrations of FT and FBAL were significantly lower with S-1 (p<0.0001 for all comparisons). Following both single-and multiple-dose administration of S-1, the average maximum DPD inhibition was observed at 4 h post-dose. The extent of inhibition was similar following single and multiple dosing. Following single- and multiple-dose administration of S-1, plasma concentrations of uracil returned to baseline levels within approximately 48 h of dosing, indicating reversibility of DPD inhibition by CDHP. Conclusion: Despite the differences in the FT dose administered, exposure to 5-FU was significantly greater following S-1 administration compared to FT administration. Conversely, exposure to FT and FBAL were significantly less following S-1 administration compared to FT administration. Thus, the DPD inhibitory action of CDHP contributes to a decrease in 5-FU catabolism and to significantly higher blood levels of 5-FU compared to FT alone.


PubMed | Taiho Pharma United States Inc
Type: Journal Article | Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology | Year: 2016

2552 Background: S-1 is a fixed combination drug composed of a prodrug of 5-FU (tegafur [FT]), a dihydropyrimidine dehydrogenase inhibitor (gimeracil [CDHP]), and an inhibitor of 5-FU phosphorylation (Oxo). Through its gastrointestinal distribution, Oxo is expected to reduce 5-FU induced GI toxicity without affecting 5-FU systemic exposure. The purpose of this study was to investigate the effect of Oxo on the PK of 5-FU by comparing the PK profile of S-1 (FT + CDHP + Oxo) to that of CFT (FT + CDHP; no Oxo).Patients with advanced refractory/relapsed solid tumors received single oral doses of S-1 and CFT (50 mg expressed as FT equivalents) orally on Day 1 and Day 8 in a randomized crossover fashion. Plasma samples were collected on Days 1 and 8 pre-dose and 0.5, 1, 2, 4, 6, 8, 10, 24 and 48 hours post-dose. Single-dose PK parameters (AUC and C28 patients were included in the PK analyses; median age was 59 years and mean BSA was 1.88 mThe presence of Oxo as a component of S-1 does not affect the systemic exposure to 5-FU. S-1 was generally well tolerated in this population. [Table: see text] [Table: see text].

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