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Mechanism of action: TS-ONE contains FT, CDHP and Oxo, and antitumor activity of TS-ONE after oral administration is based on 5-FU that appears gradually in the body via the transformation of FT. CDHP increased the concentration of 5-FU, which is converted from FT, by selectively and reversibly inhibiting DPD, a catabolic enzyme of 5-FU, which is particularly distributed in the liver. 5-fluoronucleotides, phosphorylated metabolites of 5-FU, are highly maintained in tumor tissues, thereby enhancing the antitumor activity in proportion to the increase in the concentration of 5-FU in the body. Oxo selectively inhibits the production of 5-fluoronucleotides from 5-FU by distributing in the gastrointestinal tissue as a result of oral administration and selectively and reversibly inhibiting orotate phosphoribosyltransferase. Gastrointestinal toxicity appears to be relieved as a result, without interfering with the antitumor activity of 5-FU.
The main mechanisms of action of 5-FU is the inhibition of DNA synthesis resulting from the antagonistic effect of the active metabolite FdUMP acting upon dUMP to form Ternary complex with thymidylate synthase and the reduced folic acid. RNA function is also thought to be damaged by conversion of 5-FU to FUTP, and its incorporation into RNA molecule.
Clinical Studies: Randomized phase III study of post-operative adjuvant chemotherapy: The survival benefit of TS-ONE monotherapy (one year after surgery, 529 patients) was compared with surgery alone (530 patients) in patients with stage II or III gastric cancer after curative gastrectomy (median post-operative follow-up period: 3 years). TS-ONE reduced the risk of death by 32% compared with surgery alone, with a hazard ratio for death of 0.675 (95% confidence interval: 0.523 - 0.871, p=0.0024 by the log-rank test). The three-year survival rate after surgery was 80.5% in the TS-ONE group and 70.1% in the surgery alone group. TS-ONE reduced the risk of relapse by 38% compared with surgery alone, with a hazard ratio for relapse or death of 0.622 (95% confidence interval: 0.501 - 0.772, p<0.0001 by the log-rank test). The three-year relapse-free survival rate was 72.2% in the TS-ONE group and 60.1% in the surgery alone group.
The three-year survival rate following randomization after surgery was 80.1% in the TS-ONE group and 70.1% in the surgery alone group. The three-year relapse-free survival rate following randomization after surgery was 72.2% in the TS-ONE group and 59.6% in the surgery alone group. (See Figures 1 and 2.)
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Click on icon to see table/diagram/imageTime of occurrence of adverse reactions and period of recovery: The time of occurrence of adverse reactions considered noteworthy as a result of administration of TS-ONE was analyzed in 453 patients enrolled in late clinical phase II studies of TS-ONE for advanced or recurrent cancer in Japan. The results were as follows.
Among abnormal laboratory test results below any of the criteria including a WBC count of 3000/mm3, a hemoglobin level of 8 g/dL, and a platelet count of 7.5 × 104/mm3, the median time to nadir in the cycle where the lowest level in a case was reached was 27 days for WBC count, 25 days for hemoglobin level, and 24 days for platelet count. On the other hand, in patients who were confirmed to have recovered from the previously mentioned criteria, the median between the nadir of these values and recovery from them in the course were 7 days, 5.5 days and 6 days, respectively. (See Table 3.)
Click on icon to see table/diagram/imageWhen the time of occurrence of adverse reactions after the start of the first dose of TS-ONE was examined to assess the causality between them, the median until the occurrence of diarrhea, rash and stomatitis, which were judged adverse reactions, were 24.5 days, 21 days, and 28 days, respectively. On the other hand, the median between the highest grade of these adverse reactions and the improvement from them were 9 days for diarrhea, 14 days for rash, and 13.5 days for stomatitis. (See Table 4.)
Click on icon to see table/diagram/imageAdverse reactions in the presence of renal disorder: In the post-marketing surveys of TS-ONE in patients with gastric cancer, the incidence of adverse reactions was tabulated by the range of creatinine clearance value (Ccr estimate), calculated from serum creatinine value, gender, age and weight using Cockcroft-Gault equation. The results were as follows.
In the patients, as creatinine clearance value decreased, the incidence of adverse reactions increased and the severity of the adverse reactions also increased. Additionally, in the patients who were administrated initially at the lower dose (mostly, one stage lower than the standard), the incidence of adverse reactions was low, compared with patients who were administrated initially at the standard dose. (See Table 5.)
Click on icon to see table/diagram/imagePharmacokinetics: Pharmacokinetic parameters obtained from the plasma concentrations of TS-ONE administered to 12 cancer patients in a single oral dose of 32-40 mg/m2 after a meal are shown in Table 6. The amount excreted in the urine within 72 hours after administration accounted for 52.8% of gimeracil (CDHP), 7.8% of tegafur (FT), 2.2% of oteracil potassium (Oxo), 11.4% of the metabolite cyanuric acid (CA) and 7.4% of fluorouracil (5-FU). (See Table 6.)
Click on icon to see table/diagram/imageWhen TS-ONE was orally administered at a dose of 25-200 mg/body, the AUC and Cmax of FT, CDHP, Oxo and 5-FU increased in a dose-dependent manner. When the plasma concentration of TS-ONE was measured 1, 7, 14 and 28 days after administration of 32-40 mg/m2 of TS-ONE twice a day for 28 consecutive days, it rapidly reached a constant level. Endogenous uracil (Ura) rapidly decreased even after consecutive administration of TS-ONE, and the CDHP-induced DPD inhibition was reversible, and no enhancing effect was observed.
TS-ONE, alone or in combination with other fluoropyrimidine-group drugs, was orally administered to rats for 7 consecutive days, and the plasma concentration of 5-FU was measured 2 hours after the final dose. It was found to be 4.1, 8.1, 2.8, 5.7, 6.9 and 2.3 times higher when combined with 5-FU, FT, FT-Ura, carmofur, doxifluridine and flucytosine, respectively, than when administered alone. This suggests that the combined use of TS-ONE and other fluoropyrimidine-group drugs may enhance adverse reactions.
When TS-ONE was administered to a renal dysfunction rabbit, CDHP renal clearance was found to be decreased, and the blood concentration of 5-FU was markedly increased compared to control animal. These suggest that adverse reactions may be enhanced.
Creatinine clearance value (Ccr estimate) was calculated from serum creatinine value, gender, age, and weight using the Cockcroft-Gault equation* for the clinical study patients for whom pharmacokinetics were examined in detail (clinical pharmacology, pancreatic cancer, biliary tract cancer). The AUCs of two patient groups with normal and slightly impaired renal function were tabulated by range of creatinine clearance value (Ccr estimate). (See Table 7.)
Click on icon to see table/diagram/image* Cockcroft-Gault equation: See equation.
Click on icon to see table/diagram/imageProtein binding: The rates of protein binding of each component and 5-FU in human serum were 49-56% for FT, 32-33% for CDHP, 7-10% for Oxo and 17-20% for 5-FU (in vitro).
Metabolic enzyme: It has been reported that CYP2A6 is the major cytochrome P450 isoenzymes in human liver microsomes involved in the metabolic transformation of FT to 5-FU (in vitro).
