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1.
Biol Pharm Bull ; 44(2): 266-270, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33518679

RESUMO

Extracellular pH (pHe) of tumor cells is characteristic of tumor microenvironment (TME). Acidic TME impairs the responses of tumors to some anti-cancer chemotherapies. In this study, we showed that daily oral dosing of sodium potassium citrate (K/Na citrate) increased blood HCO3- concentrations, corresponding to increase of HCO3- concentrations and pHs in urine, and neutralized the tumor pHe. Neutralization of acidic TME by alkaline substance like HCO3-, an active metabolite of K/Na citrate, well potentiated the therapeutic effect of anticancer agent TS-1®, an orally active 5-fuluoro-uracil derivative, in Panc-1 pancreatic cancer-xenograft murine model. Neutralization of acidic TME by using an alkaline K/Na citrate is a smart approach for enhancement of the therapeutic effects of anticancer agents for pancreatic cancer in the end stage.


Assuntos
Antiácidos/administração & dosagem , Concentração de Íons de Hidrogênio/efeitos dos fármacos , Ácido Oxônico/administração & dosagem , Neoplasias Pancreáticas/tratamento farmacológico , Tegafur/administração & dosagem , Microambiente Tumoral/efeitos dos fármacos , Administração Oral , Animais , Antiácidos/farmacocinética , Linhagem Celular Tumoral , Combinação de Medicamentos , Sinergismo Farmacológico , Espaço Extracelular/química , Espaço Extracelular/efeitos dos fármacos , Feminino , Humanos , Camundongos , Ácido Oxônico/farmacocinética , Ácido Oxônico/uso terapêutico , Neoplasias Pancreáticas/patologia , Citrato de Potássio/administração & dosagem , Citrato de Potássio/farmacocinética , Citrato de Sódio/administração & dosagem , Citrato de Sódio/farmacocinética , Tegafur/farmacocinética , Tegafur/uso terapêutico , Ensaios Antitumorais Modelo de Xenoenxerto
2.
Cancer Sci ; 112(2): 751-759, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33277781

RESUMO

In patients with impaired renal function, S-1-related toxicities increase due to higher exposure of 5-fluorouracil (5-FU). Our previous pharmacokinetic study in 16 cancer patients with various renal functions developed an S-1 dosage formula based on individual creatinine clearance (CLcr) and body surface area (BSA). To evaluate and refine the formula, this prospective study was conducted. Thirty-three patients with various renal functions received S-1 for 4 weeks at doses determined by the nomogram derived from the previously developed formula. A series of blood samples were collected after the first dose to calculate the area under the concentration-time curve (AUC) of 5-FU. Thirty patients with BSA of 1.14-1.84 m2 and CLcr of 23.8-96.4 mL/min were assessable for pharmacokinetics. The observed daily AUC ranged from 712.6 to 2868.7 ng·h/mL, and 18 patients achieved the target AUC (1447.8 ± 545.4 ng·h/mL). Three patients experienced S-1-related grade 3 adverse events during the first course. In the population pharmacokinetic analysis from the combined data of 46 patients in this study and the previous study, sex was identified as a statistically significant covariate for 5-FU clearance. Hence, the refined formula includes sex as an additional factor: Recommended daily dose = target AUC × (14.5 + 8.23 × SEX [0 for female and 1 for male] + 0.301 × CLcr) × BSA. Revised nomograms for recommended daily doses derived from the refined formula can be used in clinical practice to achieve the target AUC ensuring efficacy and safety of S-1.


Assuntos
Antimetabólitos Antineoplásicos/administração & dosagem , Fluoruracila/sangue , Neoplasias/tratamento farmacológico , Ácido Oxônico/administração & dosagem , Insuficiência Renal/complicações , Tegafur/administração & dosagem , Idoso , Antimetabólitos Antineoplásicos/farmacocinética , Relação Dose-Resposta a Droga , Combinação de Medicamentos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Nomogramas , Ácido Oxônico/farmacocinética , Tegafur/farmacocinética
3.
Drug Des Devel Ther ; 13: 3127-3136, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31564829

RESUMO

PURPOSE: S-1 is an oral fluoropyrimidine anticancer drug consisting of the 5-fluorouracil prodrug tegafur combined with gimeracil and oteracil. The purpose of this study was to evaluate the pharmacokinetic (PK), bioequivalence, and safety of a newly developed generic formulation of S-1 compared with the branded reference formulation, in Korean gastric cancer patients. METHODS: This was a single-center, randomized, open-label, single-dose, two-treatment, two-way crossover study. Eligible subjects were randomly assigned in a 1:1 ratio to receive the test formulation or reference formulation, followed by a one-week washout period and administration of the alternate formulation. Serial blood samples were collected at 0 hrs (predose), 0.25, 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, and 48 hrs after dosing in each period. The plasma concentrations of tegafur, 5-FU, gimeracil, and oteracil were analyzed using a validated liquid chromatography-tandem mass spectrometry method. The PK parameters were calculated using a non-compartmental method. RESULTS: In total, 29 subjects completed the study. All of the 90% confidence intervals (CIs) of the geometric mean ratios (GMRs) fell within the predetermined acceptance range. No serious adverse events were reported during the study. CONCLUSION: The new S-1 formulation met the Korean regulatory requirement for bioequivalence. Both S-1 formulations were well tolerated in all subjects.Clinical trial registry: https://cris.nih.go.kr CRIS KCT0003855.


Assuntos
Antimetabólitos Antineoplásicos/farmacocinética , Antineoplásicos/farmacocinética , Fluoruracila/farmacocinética , Ácido Oxônico/farmacocinética , Piridinas/farmacocinética , Neoplasias Gástricas/metabolismo , Tegafur/farmacocinética , Antimetabólitos Antineoplásicos/administração & dosagem , Antimetabólitos Antineoplásicos/sangue , Antineoplásicos/administração & dosagem , Antineoplásicos/sangue , Cromatografia Líquida , Estudos Cross-Over , Composição de Medicamentos , Fluoruracila/administração & dosagem , Fluoruracila/sangue , Humanos , Ácido Oxônico/administração & dosagem , Ácido Oxônico/sangue , Piridinas/administração & dosagem , Piridinas/sangue , República da Coreia , Neoplasias Gástricas/química , Espectrometria de Massas em Tandem , Tegafur/administração & dosagem , Tegafur/sangue , Equivalência Terapêutica
4.
Cancer Sci ; 110(6): 1987-1994, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30989775

RESUMO

Although dose reduction of S-1 is recommended for patients with impaired renal function, dose modification for such patients has not been prospectively evaluated. The aim of the present study was to investigate the pharmacokinetic parameters of 5-fluorouracil, 5-chloro-2,4 dihydroxypyridine and oteracil potassium, and to review the recommended dose modification of S-1 in patients with renal impairment. We classified patients receiving S-1 into 4 groups according to their renal function, as measured using the Japanese estimated glomerular filtration rate (eGFR) equation. The daily S-1 dose was adjusted based on the patient's eGFR and body surface area. Blood samples were collected for pharmacokinetic analysis. A total of 33 patients were enrolled and classified into 4 groups as follows: 10 patients in cohort 1 (eGFR ≥ 80 mL/min/1.73 m2 ), 10 patients in cohort 2 (eGFR = 50-79 mL/min/1.73 m2 ), 10 patients in cohort 3 (eGFR = 30-49 mL/min/1.73 m2 ), and 3 patients in cohort 4 (eGFR < 30 mL/min/1.73 m2 ). Those in cohorts 3 and 4 treated with an adjusted dose of S-1 showed a similar area under the curve for 5-fluorouracil (941.9 ± 275.6 and 1043.5 ± 224.8 ng/mL, respectively) compared with cohort 2 (1034.9 ± 414.3 ng/mL). Notably, while there was a statistically significant difference between cohort 1 (689.6 ± 208.8 ng/mL) and 2 (P = 0.0474) treated with an equal dose of S-1, there was no significant difference observed in the toxicity profiles of the cohorts. In conclusion, dose adjustment of S-1 in patients with impaired renal function using eGFR is appropriate and safe.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Insuficiência Renal/tratamento farmacológico , Neoplasias Gástricas/tratamento farmacológico , Administração Oral , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Área Sob a Curva , Estudos de Coortes , Combinação de Medicamentos , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/efeitos adversos , Fluoruracila/farmacocinética , Taxa de Filtração Glomerular/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Náusea/induzido quimicamente , Ácido Oxônico/administração & dosagem , Ácido Oxônico/efeitos adversos , Ácido Oxônico/farmacocinética , Insuficiência Renal/complicações , Insuficiência Renal/metabolismo , Neoplasias Gástricas/complicações , Neoplasias Gástricas/metabolismo , Tegafur/administração & dosagem , Tegafur/efeitos adversos , Tegafur/farmacocinética
5.
Int J Clin Oncol ; 24(6): 660-665, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31011915

RESUMO

BACKGROUND: S-1 is an oral anticancer drug composed of tegafur (FT), which is a prodrug of 5-FU, 5-chloro-2,4-dihydroxypyridine (CDHP), and potassium oxonate. Recently, some studies have been reported on watering eyes caused by S-1. However, the mechanism of watering eyes caused by S-1 is still unclear. The aim of this study was to investigate the correlation between tears and plasma concentrations of FT, 5-FU, and CDHP, which are components and active modulator of S-1. METHODS: We prospectively investigated the pharmacokinetics (PK) of FT, 5-FU, and CDHP in plasma and in tears of gastric cancer patients who were treated with S-1 monotherapy at the dose of 80 mg/m2/day. Plasma and tears from both eyes were obtained 1, 2, 4, and 8 h after S-1 administration on day 1 and 14 of the first cycle. RESULTS: Total of eight patients were enrolled. All the FT, 5-FU and CDHP were detected both in plasma and in tears, and their PK parameters were measured. There was a positive correlation between the concentrations of FT, 5-FU and CDHP in the plasma and those in the tears on day 1 and day 14 (correlation coefficients r, right eye/left eye: r = 0.882/0.878, 0.877/0.890, and 0.885/0.878, respectively). CONCLUSION: There was a positive correlation between the concentrations of FT, 5-FU and CDHP in the plasma and those in the tears. The result is expected to facilitate the further investigation into the causes of watering eyes and the establishment of the effective methods for the prevention and the treatment.


Assuntos
Ácido Oxônico/farmacocinética , Ácido Oxônico/uso terapêutico , Plasma/metabolismo , Neoplasias Gástricas/tratamento farmacológico , Lágrimas/metabolismo , Tegafur/farmacocinética , Tegafur/uso terapêutico , Adulto , Idoso , Combinação de Medicamentos , Feminino , Fluoruracila/análise , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Piridinas/análise , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Tegafur/análise , Distribuição Tecidual
6.
Invest New Drugs ; 37(3): 507-518, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30511200

RESUMO

Background This first-in-human phase 1 study assessed the safety of TAS-114, a novel deoxyuridine triphosphatase inhibitor, combined with S-1 to determine its maximum tolerated dose (MTD) and recommended dose (RD). Methods In this dose-escalation study with a 3 + 3 design, TAS-114 and S-1 were concurrently administered orally under fasting conditions at 5-240 mg/m2 and 30-36 mg/m2, respectively, in patients with advanced solid tumors. Safety, efficacy, and pharmacokinetics (PK) were evaluated. Results Seventy-six patients were enrolled. The MTD and RD were TAS-114 200 mg/m2 plus S-1 36 mg/m2 and TAS-114 240 mg/m2 plus S-1 30 mg/m2, respectively. Common treatment-related adverse events were anemia, lymphocytopenia, leukopenia, neutropenia, decreased appetite, rash, nausea, and pigmentation disorder. Partial response (PR) was observed in 10 patients (non-small cell lung cancer [NSCLC], n = 5; pancreatic neuroendocrine tumor, n = 2; gastric cancer, n = 2; gallbladder cancer, n = 1). Of these, four patients achieved PR despite prior treatment history with S-1. Patients administered TAS-114 exhibited linear PK and CYP3A4 induction, with no effect on the PK of S-1. Conclusion TAS-114 plus S-1 showed tolerable, safe, and potentially effective results. To confirm safety and efficacy, two phase 2 studies are ongoing in NSCLC and gastric cancer patients. Clinical trial registration ClinicalTrials.gov ( NCT01610479 ) .


Assuntos
Antimetabólitos Antineoplásicos/uso terapêutico , Inibidores Enzimáticos/uso terapêutico , Neoplasias/tratamento farmacológico , Ácido Oxônico/uso terapêutico , Pirimidinas/uso terapêutico , Pirofosfatases/antagonistas & inibidores , Sulfonamidas/uso terapêutico , Tegafur/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antimetabólitos Antineoplásicos/farmacocinética , Combinação de Medicamentos , Quimioterapia Combinada , Inibidores Enzimáticos/farmacocinética , Feminino , Seguimentos , Humanos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Neoplasias/patologia , Ácido Oxônico/farmacocinética , Prognóstico , Pirimidinas/farmacocinética , Sulfonamidas/farmacocinética , Tegafur/farmacocinética , Distribuição Tecidual
7.
Cancer Chemother Pharmacol ; 81(3): 461-468, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29305639

RESUMO

PURPOSE: To determine the recommended dose (RD) of gemcitabine (GEM) plus S-1 (GS) in curatively resected biliary tract cancer (BTC) patients without major hepatectomy. METHODS: A standard 3 + 3 dose-escalation design was used with planned dose levels (mg/m2) of GEM (administered intravenously on days 1 and 8) and S-1 (administered orally twice daily on days 1-14, with a 1-week rest, every 3 weeks for up to 24 weeks) of 1000/80 (Level 2), 1000/65 (Level 1), 800/65 (Level - 1), and 800/50 (Level - 2). RESULTS: Thirty-one patients (17 men and 14 women; median age, 70 years) were enrolled. Level 1 was chosen as the starting dose. Three of seven patients developed dose-limiting toxicities at Level 1 and the dose was de-escalated to Level - 1. Five of 12 patients developed Grade 4 neutropenia at Level - 1 and the dose was de-escalated to Level - 2. One patient developed Grade 4 neutropenia at Level - 2. Another patient was unable to receive the day 8 dose due to Grade 3 neutropenia at Level - 2. Level - 1 was confirmed as the maximum tolerated dose and Level - 2 the RD for this regimen. The 1- and 2-year recurrence-free survival rates were 77.0 and 54.0%, respectively. The recurrence-free survival rate of patients in the GS completion group was significantly higher than that of the GS discontinuation group. CONCLUSIONS: Level - 2 was confirmed as the RD (GEM 800 mg/m2 and S-1 50 mg/m2) for GS adjuvant chemotherapy in curatively resected BTC patients without major hepatectomy.


Assuntos
Neoplasias do Sistema Biliar/tratamento farmacológico , Procedimentos Cirúrgicos do Sistema Biliar/métodos , Desoxicitidina/análogos & derivados , Monitoramento de Medicamentos/métodos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Ácido Oxônico , Tegafur , Administração Intravenosa , Idoso , Antimetabólitos Antineoplásicos/administração & dosagem , Antimetabólitos Antineoplásicos/efeitos adversos , Antimetabólitos Antineoplásicos/farmacocinética , Neoplasias do Sistema Biliar/patologia , Neoplasias do Sistema Biliar/cirurgia , Quimioterapia Adjuvante/métodos , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Desoxicitidina/farmacocinética , Relação Dose-Resposta a Droga , Esquema de Medicação , Combinação de Medicamentos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/diagnóstico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/etiologia , Feminino , Humanos , Masculino , Dose Máxima Tolerável , Ácido Oxônico/administração & dosagem , Ácido Oxônico/efeitos adversos , Ácido Oxônico/farmacocinética , Análise de Sobrevida , Tegafur/administração & dosagem , Tegafur/efeitos adversos , Tegafur/farmacocinética , Resultado do Tratamento , Gencitabina
8.
Cancer Med ; 6(12): 2909-2917, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29131533

RESUMO

S-1 and irinotecan combination is attractive for breast cancer refractory to anthracyclines and taxanes. Patients with advanced human epidermal growth factor receptor 2 (HER2)-negative breast cancer previously treated with anthracyclines and taxanes were eligible. Patients with brain metastases and homozygous for UGT1A1 *6 or *28 or compound heterozygous (*6/*28) were excluded. A dose-escalation design was chosen for the phase I portion (level 1: irinotecan 80 mg/m2  days 1-8 and S-1 80 mg/m2  days 1-14 every 3 weeks; level 2: irinotecan 100 mg/m2 and S-1 80 mg/m2 ). Study objectives included determination of the recommended dose for phase II, response rate, progression-free survival (PFS), and safety. Pharmacokinetics and CD34+ circulating endothelial cells (CECs) as pharmacodynamics were also analyzed. Thirty-seven patients were included. One patient at each level developed dose-limiting toxicities; therefore, level 2 was the recommended dose for phase II. Diarrhea was more common in patients possessing a *6 or *28 allele compared with wild-type homozygous patients (46% and 25%). Among 29 patients treated at level 2, PFS was longer for UGT1A1 wt/*6 and wt/*28 patients than for wt/wt patients (12 vs. 8 months, P = 0.06). PFS was significantly longer in patients with a larger-than-median SN-38 area under the curve (AUC) than in those with a smaller AUC (P = 0.039). There was an association between clinical benefit and reduction in baseline CD34+ CECs by S-1 (P = 0.047). The combination of irinotecan and S-1 is effective and warrants further investigation.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Neoplasias da Mama/tratamento farmacológico , Camptotecina/análogos & derivados , Glucuronosiltransferase/genética , Recidiva Local de Neoplasia , Ácido Oxônico/farmacocinética , Variantes Farmacogenômicos , Tegafur/farmacocinética , Adulto , Idoso , Antígenos CD34/sangue , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/enzimologia , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Camptotecina/administração & dosagem , Camptotecina/efeitos adversos , Camptotecina/farmacocinética , Intervalo Livre de Doença , Esquema de Medicação , Combinação de Medicamentos , Células Progenitoras Endoteliais/efeitos dos fármacos , Células Progenitoras Endoteliais/metabolismo , Células Progenitoras Endoteliais/patologia , Feminino , Frequência do Gene , Glucuronosiltransferase/metabolismo , Heterozigoto , Homozigoto , Humanos , Irinotecano , Japão , Pessoa de Meia-Idade , Metástase Neoplásica , Ácido Oxônico/administração & dosagem , Ácido Oxônico/efeitos adversos , Farmacogenética , Fenótipo , Tegafur/administração & dosagem , Tegafur/efeitos adversos , Resultado do Tratamento
9.
Molecules ; 22(9)2017 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-28880240

RESUMO

S-1 (TS-1®) is an oral fluoropyrimidine anticancer agent containing tegafur, oteracil, and gimeracil. Sipjeondaebo-tang (SDT) is a traditional oriental herbal medicine that has potential to alleviate chemotherapy-related adverse effects. The aim of the present study was to evaluate the effect of SDT on the pharmacokinetics of S-1. Sprague-Dawley rats were pretreated with a single dose or repeated doses of SDT for seven consecutive days (1200 mg/kg/day). After the completion of pretreatment with SDT, S-1 was orally administered and plasma concentrations of tegafur, its active metabolite 5-FU, and gimeracil were determined by liquid chromatography-tandem mass spectrometry (LC/MS/MS). A population pharmacokinetic model was developed to evaluate the effect of SDT on pharmacokinetics of tegafur and 5-FU. Although a single dose of SDT did not have any significant effect, the absorption rate of tegafur decreased, and the plasma levels of 5-FU reduced significantly in rats pretreated with SDT for seven days in parallel to the decreased gimeracil concentrations. Population pharmacokinetic modeling also showed the enhanced elimination of 5-FU in the SDT-pretreated group. Repeated doses of SDT may inhibit the absorption of gimeracil, an inhibitor of 5-FU metabolism, resulting in enhanced elimination of 5-FU and decrease its plasma level.


Assuntos
Antimetabólitos Antineoplásicos/farmacocinética , Medicamentos de Ervas Chinesas/farmacologia , Ácido Oxônico/farmacocinética , Piridinas/farmacocinética , Tegafur/farmacocinética , Administração Oral , Animais , Antimetabólitos Antineoplásicos/química , Combinação de Medicamentos , Medicamentos de Ervas Chinesas/administração & dosagem , Medicamentos de Ervas Chinesas/química , Fluoruracila/metabolismo , Interações Ervas-Drogas , Humanos , Masculino , Modelos Biológicos , Ácido Oxônico/química , Piridinas/química , Ratos Sprague-Dawley , Tegafur/química
10.
Cancer Sci ; 108(10): 2045-2051, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28763145

RESUMO

A phase II study of S-1 plus leucovorin (LV) given in a 4-week schedule (2 weeks' administration followed by 2 weeks' rest) for patients with untreated metastatic colorectal cancer (mCRC) showed that the combination was effective, but grade 3 toxicities (diarrhea, stomatitis and anorexia) occurred at a relatively high rate. In this phase II study, we evaluated the efficacy and safety of a 2-week schedule of S-1 plus LV. Patients with mCRC received oral S-1 (40-60 mg) and LV (25 mg) twice daily for 1 week, followed by 1 week's rest. Treatment was repeated until disease progression or unacceptable toxicity. The primary endpoint was response rate. The pharmacokinetics of S-1 and LV in Chinese patients were evaluated on day 1 of the first cycle. Seventy-three patients were enrolled in Japan and China. Of 71 eligible patients, the response rate was 53.5%, and the disease control rate was 83.1%. Median progression-free survival and median overall survival were 6.5 and 24.3 months, respectively. The incidences of grade 3 toxicities were diarrhea 8.3%, stomatitis 8.3%, anorexia 2.8% and neutropenia 9.7%. There were no treatment-related deaths. The pharmacokinetics profiles of S-1 plus LV in Chinese patients were similar to those in Japanese patients. This 2-week schedule of S-1 plus LV showed good efficacy and better tolerability than the 4-week schedule. This therapy will be the base regimen for mCRC to be added by other cytotoxic or molecular-targeted drugs. The optimized treatment schedule for S-1 plus LV was 1 week on and 1 week off.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias Colorretais/tratamento farmacológico , Leucovorina/administração & dosagem , Ácido Oxônico/administração & dosagem , Tegafur/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Anorexia/induzido quimicamente , Anorexia/epidemiologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , China , Diarreia/induzido quimicamente , Diarreia/epidemiologia , Esquema de Medicação , Combinação de Medicamentos , Feminino , Humanos , Japão , Leucovorina/efeitos adversos , Leucovorina/farmacocinética , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Neutropenia/induzido quimicamente , Neutropenia/epidemiologia , Ácido Oxônico/efeitos adversos , Ácido Oxônico/farmacocinética , Estomatite/induzido quimicamente , Estomatite/epidemiologia , Análise de Sobrevida , Tegafur/efeitos adversos , Tegafur/farmacocinética , Resultado do Tratamento
11.
Jpn J Clin Oncol ; 47(5): 407-412, 2017 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-28159957

RESUMO

BACKGROUND: S-1 is a combination of tegafur [metabolized to 5-fluorouracil (5-FU)] with the modulators gimeracil (5-chloro-2,4-dihydroxypyridine) and oteracil potassium. 5-Chloro-2,4-dihydroxypyridine maintains plasma 5-FU concentrations by inhibiting dihydropyrimidine dehydrogenase, a pyrimidine catabolism enzyme that degrades 5-FU. As 50% of 5-chloro-2,4-dihydroxypyridine is excreted in urine, renal insufficiency may increase its blood level, increasing 5-FU concentrations. We investigated whether special dose modification is needed in the presence of renal insufficiency. OBJECTIVE: We compared steady state pharmacokinetics of 5-FU for the initial S-1 dose and reduced doses in patients with head and neck cancer requiring dose reduction due to renal and non-renal toxicities. METHODS: Chemoradiotherapy with S-1 and cisplatin was administered every 5 weeks for two courses with a radiation dose totaling 70 Gy over 33-35 fractions. Two additional courses of adjuvant chemotherapy were administered in the case of an objective response. The S-1 and/or cisplatin dose was reduced in response to renal, hematologic or other toxicities. The primary endpoint was the change in area under the plasma concentration-versus-time curve from time 0-10 hours (5-FU AUCss 0-10) between the initial and reduced S-1 doses. RESULTS: Although the mean 5-FU levels in patients with non-renal toxicities significantly decreased between the full and reduced dose, the full-dose and reduced-dose mean maximum 5-FU plasma concentrations at steady state (Css max) and AUCss 0-10 in patients with renal insufficiency were similar. CONCLUSIONS: Standard S-1 dose reduction for renal toxicity did not result in a significant decrease in 5-FU levels at steady state. A greater reduction to lower plasma 5-chloro-2,4-dihydroxypyridine may be necessary in patients with renal insufficiency.


Assuntos
Neoplasias de Cabeça e Pescoço/complicações , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Ácido Oxônico/farmacocinética , Ácido Oxônico/uso terapêutico , Insuficiência Renal/complicações , Tegafur/farmacocinética , Tegafur/uso terapêutico , Idoso , Área Sob a Curva , Cisplatino/farmacologia , Cisplatino/uso terapêutico , Relação Dose-Resposta a Droga , Combinação de Medicamentos , Feminino , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Rim/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias
12.
Cancer Chemother Pharmacol ; 79(1): 107-116, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-27933371

RESUMO

PURPOSE: S-1 has shown a response rate of 35% in chemonaïve patients with metastatic colorectal cancer (mCRC). Leucovorin enhances the antitumor activity of 5-fluorouracil, and concurrent oral administration of S-1 and leucovorin may represent a more active treatment option for mCRC. METHODS: S-1 (35 mg/m2) and leucovorin (25 mg/body) were orally administered twice daily to chemonaïve patients with mCRC. Predefined dose (schedule)-limiting toxicities (DLTs) during the first course and treatment continuity during the first two courses were evaluated during three periods of treatment with S-1 plus leucovorin (level 0, 2 weeks; level 1, 3 weeks; and level 2, 4 weeks), each followed by a 2-week rest. The pharmacokinetics (PK) of S-1 and leucovorin were studied on days 1 and 14 of the first course. RESULTS: Fifteen patients were enrolled. All three patients had DLTs at level 2, and this level was considered the maximum tolerated schedule. Level 0 was designated as the recommended schedule based on the incidences of DLTs and treatment continuity. The main toxic effects were gastrointestinal, such as diarrhea and stomatitis. There was no grade 4 adverse event or treatment-related death. The overall response rate was 67% (95% confidence interval, 38-88%). The PK profiles of S-1 plus leucovorin were similar to those in previous studies. CONCLUSIONS: The recommended schedule was 2 weeks of S-1 plus leucovorin followed by a 2-week rest. The increased response and gastrointestinal toxicities of S-1 plus leucovorin as compared with S-1 monotherapy suggest that co-administration of leucovorin enhanced the activity of S-1.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Administração Oral , Adulto , Idoso , Combinação de Medicamentos , Feminino , Humanos , Leucovorina/administração & dosagem , Leucovorina/efeitos adversos , Leucovorina/farmacocinética , Masculino , Pessoa de Meia-Idade , Ácido Oxônico/administração & dosagem , Ácido Oxônico/efeitos adversos , Ácido Oxônico/farmacocinética , Tegafur/administração & dosagem , Tegafur/efeitos adversos , Tegafur/farmacocinética
13.
Gastric Cancer ; 19(3): 876-86, 2016 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-26304171

RESUMO

BACKGROUND: S-1 is an oral anticancer drug, containing tegafur (a prodrug of 5-fluorouracil, 5-FU), 5-chloro-2,4-dihydroxypyridine, and potassium oxonate. As renal dysfunction is known to increase exposure of 5-FU following S-1 administration, the incidence of severe adverse reactions is increased in patients with impaired renal function. However, no reliable information on its dose modification for patients with renal dysfunction has been provided. METHODS: We conducted a prospective pharmacokinetic study to develop an S-1 dosage formula based on renal function. Sixteen cancer patients with various degrees of renal function received a single dose of S-1 at 40 mg/m(2). A series of blood samples were collected at predefined times within 24 h to assess the plasma concentration profiles of 5-FU, 5-chloro-2,4-dihydroxypyridine, and tegafur. A mathematical model for the relationship between renal function and exposure of 5-FU was constructed by a population pharmacokinetic analysis. RESULTS: The clearance of 5-FU following S-1 administration was related to body surface area and creatinine clearance in the range 15.9-108.8 mL/min as estimated by the Cockcroft-Gault equation. The S-1 dosage formula was derived as follows:[Formula: see text]where AUC is the area under the concentration-time curve, CLcr is creatinine clearance, and BSA is body surface area. The recommended daily doses of S-1 in Asia and Europe were also proposed as nomograms according to exposure matching to the previously reported area under the concentration-time curve of 5-FU, which confirmed the efficacy and toxicity in pivotal registration studies. CONCLUSIONS: We have developed a novel formula for determining the S-1 dosage on the basis of renal function. Further validation is needed to confirm the formula for practical application.


Assuntos
Antimetabólitos Antineoplásicos/farmacocinética , Fluoruracila/farmacocinética , Ácido Oxônico/farmacocinética , Insuficiência Renal/sangue , Neoplasias Gástricas/tratamento farmacológico , Tegafur/farmacocinética , Idoso , Antimetabólitos Antineoplásicos/administração & dosagem , Antimetabólitos Antineoplásicos/efeitos adversos , Combinação de Medicamentos , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Ácido Oxônico/administração & dosagem , Ácido Oxônico/efeitos adversos , Prognóstico , Estudos Prospectivos , Insuficiência Renal/induzido quimicamente , Neoplasias Gástricas/sangue , Tegafur/administração & dosagem , Tegafur/efeitos adversos , Distribuição Tecidual
14.
J Clin Pharmacol ; 55(8): 926-35, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25810324

RESUMO

S-1 is an oral 5-fluorouracil agent containing tegafur, 5-chloro-2, 4-dihydroxypyridine (CDHP), and potassium oxonate. This study explored the pharmacokinetics of S-1 and pharmacokinetic changes after gastric surgery in patients with resectable gastric cancer who received pre- and postoperative S-1 plus docetaxel. Serial blood was drawn before and after gastrectomy from 37 patients for pharmacokinetic analysis. The pharmacokinetics of tegafur, 5-fluorouracil, and CDHP were analyzed by noncompartmental analysis (NCA) methods and by modeling. In modeling analysis, CHDP concentrations were incorporated in the model as a time-varying covariate that inhibits the clearance of 5-fluorouracil following an inhibitory Emax model. In NCA, the pharmacokinetics of tegafur and 5-FU before and after gastric surgery were similar, although average maximum concentrations of 5-FU were decreased with statistical significance after gastrectomy. Median Tmax of tegafur was shorter after surgery without statistical significance. In modeling analysis, tegafur was best fitted by mixed zero and first-order absorption. The only difference in the final pharmacokinetic model around gastrectomy was the presence of an absorption lag of 0.23 hours before surgery. Incorporation of CDHP concentrations significantly improved the model. Although some pharmacokinetic results showed statistically significant changes after gastrectomy, these differences seem to be too small to have any clinical implication.


Assuntos
Antimetabólitos Antineoplásicos/farmacocinética , Ácido Oxônico/farmacocinética , Neoplasias Gástricas/metabolismo , Tegafur/farmacocinética , Adulto , Idoso , Antimetabólitos Antineoplásicos/sangue , Combinação de Medicamentos , Feminino , Gastrectomia , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Ácido Oxônico/sangue , Piridinas/sangue , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/cirurgia , Tegafur/sangue
15.
Cancer Sci ; 106(6): 734-739, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25786335

RESUMO

We conducted a phase I study of a weekly nab-paclitaxel and S-1 combination therapy in patients with human epidermal growth factor receptor type 2-negative metastatic breast cancer. The primary objective was to estimate the maximum tolerated and recommended doses. Each treatment was repeated every 21 days. Levels 1, 2a, 2b, and 3 were set depending on the S-1 dose (65 or 80 mg/m(2) ) and nab-paclitaxel infusion schedule (days 1 and 8 or days 1, 8, and 15). Fifteen patients were enrolled. Dose-limiting toxicity was observed in one patient at Level 3 (100 mg/m(2) nab-paclitaxel on days 1, 8, and 15 with 80 mg/m(2) S-1 daily for 14 days, followed by 7 days of rest). Although the maximum tolerated dose was not reached, the recommended dose was determined to be Level 3. Neutropenia was the most frequent grade 3-4 treatment-related adverse event. For patients with measurable lesions, the response rate was 50.0% and the median time to treatment failure and median progression-free survival was 13.2 and 21.0 months, respectively. The present results show the feasibility and potential for long-term administration of this combination therapy.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Receptor ErbB-2/análise , Adulto , Idoso , Albuminas/administração & dosagem , Albuminas/efeitos adversos , Albuminas/farmacocinética , Neoplasias da Mama/química , Neoplasias da Mama/mortalidade , Esquema de Medicação , Combinação de Medicamentos , Feminino , Humanos , Pessoa de Meia-Idade , Ácido Oxônico/administração & dosagem , Ácido Oxônico/efeitos adversos , Ácido Oxônico/farmacocinética , Paclitaxel/administração & dosagem , Paclitaxel/efeitos adversos , Paclitaxel/farmacocinética , Tegafur/administração & dosagem , Tegafur/efeitos adversos , Tegafur/farmacocinética
16.
Br J Cancer ; 112(5): 819-24, 2015 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-25654665

RESUMO

BACKGROUND: We evaluated the safety, maximum-tolerated dose (MTD), pharmacokinetics, recommended dose for phase II (P2RD), and preliminary anticancer activity of a combination eribulin and S-1 therapeutic in metastatic breast cancer patients pretreated with anthracycline and taxane. METHOD: Patients aged 20-74 years were recruited. In level 1, patients received S-1 (65 mg m(-2)) from day 1 to 14, and eribulin (1.1 mg m(-2)) on day 1 and 8 in a 21-day cycle. In level 2, eribulin was increased to 1.4 mg m(-2). In level 3, S-1 was increased to 80 mg m(-2). RESULTS: Twelve patients were enrolled into three cohorts. Planned dose escalation was completed, with one case exhibiting dose-limiting toxicity (grade 3 hypokalaemia) at level 3, without reaching the MTD. The P2RD was determined to be level 2 (eribulin 1.4 mg m(-2) and S-1 65 mg m(-2)). The most common grade 3 or 4 toxicity was neutropenia (83.3%), followed by febrile neutropenia (25.0%). Five of eleven patients (41.7%) with measurable disease had a partial response. Pharmacokinetics were characterised by dose-dependent elimination and nonlinear exposure. CONCLUSION: Dose level 3 was not tolerated owing to febrile neutropenia development. Thus, intermediate dose level 2 was recommended for further evaluation. Preliminary antitumour activity warrants further investigation in this setting.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Furanos/administração & dosagem , Furanos/farmacocinética , Cetonas/administração & dosagem , Cetonas/farmacocinética , Ácido Oxônico/administração & dosagem , Ácido Oxônico/farmacocinética , Tegafur/administração & dosagem , Tegafur/farmacocinética , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Relação Dose-Resposta a Droga , Esquema de Medicação , Combinação de Medicamentos , Feminino , Furanos/uso terapêutico , Humanos , Cetonas/uso terapêutico , Dose Máxima Tolerável , Pessoa de Meia-Idade , Metástase Neoplásica/tratamento farmacológico , Ácido Oxônico/uso terapêutico , Tegafur/uso terapêutico , Adulto Jovem
17.
Cancer Chemother Pharmacol ; 74(6): 1321-4, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25374410

RESUMO

PURPOSE: The safety of S-1 in recurrent colorectal cancer patients with chronic myeloid leukemia (CML) treated with dasatinib has not been established. We evaluated the safety and pharmacokinetics of S-1 in a recurrent colon cancer patient with CML treated with dasatinib. PATIENT: A 70-year-old man had undergone surgery three times for sigmoid colon cancer and recurrence. Systemic chemotherapy with S-1 plus oxaliplatin plus bevacizumab as a clinical trial had already been administered because of metastatic colon cancer. The patient's medical history was CML, and he had been receiving dasatinib treatment (100 mg once daily). Based on the diagnosis of unresectable and multiple metastases, S-1 monotherapy was started. S-1 (120 mg/day) was taken for 28 consecutive days, followed by a 14-day rest. Blood samples were obtained before and after the first administration of S-1. The plasma pharmacokinetics of S-1 were comparable to a pharmacokinetics study of S-1. RESULTS: The area under the plasma concentration-time curve (AUC0-8) of tegafur (FT), 5-chloro-2, 4-dihydroxypyridine (CDHP), oxonate (Oxo), and 5-fluorouracil (5-FU) was 4,309.2, 716.3, 86.8, and 492.75 ng h/mL, respectively, after S-1 administration. The pharmacokinetics of FT, CDHP, Oxo, and 5-FU after treatment with S-1 were not significantly different from a phase I pharmacokinetics study of S-1. During treatment with S-1 and dasatinib, CML relapse and serious myelosuppression were not observed. CONCLUSIONS: Our report suggests that S-1 is an important treatment option for recurrent colorectal cancer in patients with CML treated with dasatinib.


Assuntos
Antimetabólitos Antineoplásicos/uso terapêutico , Neoplasias do Colo/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Ácido Oxônico/uso terapêutico , Tegafur/uso terapêutico , Idoso , Antimetabólitos Antineoplásicos/efeitos adversos , Antimetabólitos Antineoplásicos/farmacocinética , Área Sob a Curva , Neoplasias do Colo/patologia , Dasatinibe , Combinação de Medicamentos , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Masculino , Metástase Neoplásica , Recidiva Local de Neoplasia , Ácido Oxônico/efeitos adversos , Ácido Oxônico/farmacocinética , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/uso terapêutico , Tegafur/efeitos adversos , Tegafur/farmacocinética , Tiazóis/uso terapêutico
18.
Invest Clin ; 55(2): 185-202, 2014 Jun.
Artigo em Espanhol | MEDLINE | ID: mdl-24974634

RESUMO

Gastric cancer (GC) is often diagnosed at later stages due to the lack of specificity of symptoms associated with the neoplasm, causing high mortality rates worldwide. The first line of adjuvant and neoadjuvant treatment includes cytotoxic fluoropyrimidines and platin-containing compounds which cause the formation of DNA adducts. The clinical outcome with these antineoplastic agents depends mainly on tumor sensitivity, which is conditioned by the expression level of the drug targets and the DNA-repair system enzymes. In addition, some germ line polymorphisms, in genes linked to drug metabolism and response to chemotherapy, have been associated with poor responses and the development of adverse effects, even with fatal outcomes in GC patients. The identification of genomic biomarkers, such as individual gene polymorphisms or differential expression patterns of specific genes, in a patient-by-patient context with potential clinical application is the main focus of current pharmacogenomic research, which aims at developing a rational and personalized therapy (i.e., a therapy that ensures maximum efficacy with no predictable side effects). However, because of the future application of genomic technologies in the clinical setting, it is necessary to establish the prognostic value of these genomic biomarkers with genotype-phenotype association studies and to evaluate their prevalence in the population under treatment. These issues are important for their cost-effectiveness evaluation, which determines the feasibility of using these medical genomic research products for GC treatment in the clinical setting.


Assuntos
Antineoplásicos/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Gástricas/tratamento farmacológico , Antineoplásicos/efeitos adversos , Antineoplásicos/classificação , Transporte Biológico/genética , Biomarcadores , Biotransformação/genética , Capecitabina , Terapia Combinada , Desoxicitidina/efeitos adversos , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacocinética , Desoxicitidina/uso terapêutico , Combinação de Medicamentos , Resistencia a Medicamentos Antineoplásicos/genética , Enzimas/genética , Etnicidade/genética , Fluoruracila/efeitos adversos , Fluoruracila/análogos & derivados , Fluoruracila/farmacocinética , Fluoruracila/uso terapêutico , Gastrectomia , Humanos , México , Terapia de Alvo Molecular , Compostos Organoplatínicos/farmacocinética , Ácido Oxônico/farmacocinética , Seleção de Pacientes , Farmacogenética , Medicina de Precisão , Pró-Fármacos/farmacocinética , Neoplasias Gástricas/genética , Neoplasias Gástricas/cirurgia , Tegafur/farmacocinética
19.
Invest. clín ; 55(2): 185-202, jun. 2014. ilus, tab
Artigo em Espanhol | LILACS | ID: lil-749976

RESUMO

Debido a la inespecificidad de los síntomas, el cáncer gástrico (CG) es diagnosticado frecuentemente en etapas avanzadas, lo que da cuenta de los altos índices de mortalidad debido a esta neoplasia a nivel mundial. El esquema de tratamiento adyuvante o neoadyuvante en los países occidentales incluye el uso de fluoropirimidinas citotóxicas y compuestos de platino formadores de aductos en el ADN. La respuesta clínica al tratamiento con estos fármacos depende principalmente de la sensibilidad del tumor, la cual a su vez está condicionada por el nivel de expresión de los blancos terapéuticos y de las enzimas de reparación del ADN. Sumado a esto, algunos polimorfismos de línea germinal en genes asociados al metabolismo y a la respuesta a estos fármacos, han mostrado asociación con respuestas pobres y con el desarrollo de eventos adversos, incluso con resultados fatales. La identificación de biomarcadores genómicos, en la forma de polimorfismos genéticos o la expresión diferencial de genes específicos asociados a la respuesta quimioterapeútica ha sido motivo de intensa investigación como base para la aplicación de la farmacogenómica en el establecimiento de una terapia farmacológica racional y personalizada del CG. Sin embargo, ante la eventual aplicación de la farmacogenómica en el ámbito clínico, es necesario establecer el valor pronóstico real de dichos biomarcadores mediante los estudios de asociación genotipo-fenotipo, así como su prevalencia en el contexto de cada población de pacientes. Estos aspectos son indispensables al evaluar la relación costo-efectividad de la introducción de los productos de la medicina genómica predictiva en el tratamiento del CG.


Gastric cancer (GC) is often diagnosed at later stages due to the lack of specificity of symptoms associated with the neoplasm, causing high mortality rates worldwide. The first line of adjuvant and neoadjuvant treatment includes cytotoxic fluoropyrimidines and platin-containing compounds which cause the formation of DNA adducts. The clinical outcome with these antineoplastic agents depends mainly on tumor sensitivity, which is conditioned by the expression level of the drug targets and the DNA-repair system enzymes. In addition, some germ line polymorphisms, in genes linked to drug metabolism and response to chemotherapy, have been associated with poor responses and the development of adverse effects, even with fatal outcomes in GC patients. The identification of genomic biomarkers, such as individual gene polymorphisms or differential expression patterns of specific genes, in a patient-by-patient context with potential clinical application is the main focus of current pharmacogenomic research, which aims at developing a rational and personalized therapy (i.e., a therapy that ensures maximum efficacy with no predictable side effects). However, because of the future application of genomic technologies in the clinical setting, it is necessary to establish the prognostic value of these genomic biomarkers with genotype-phenotype association studies and to evaluate their prevalence in the population under treatment. These issues are important for their cost-effectiveness evaluation, which determines the feasibility of using these medical genomic research products for GC treatment in the clinical setting.


Assuntos
Humanos , Antineoplásicos/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Gástricas/tratamento farmacológico , Antineoplásicos/efeitos adversos , Antineoplásicos/classificação , Biomarcadores , Transporte Biológico/genética , Biotransformação/genética , Terapia Combinada , Combinação de Medicamentos , Desoxicitidina/efeitos adversos , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacocinética , Desoxicitidina/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/genética , Enzimas/genética , Etnicidade/genética , Fluoruracila/efeitos adversos , Fluoruracila/análogos & derivados , Fluoruracila/farmacocinética , Fluoruracila/uso terapêutico , Gastrectomia , México , Terapia de Alvo Molecular , Compostos Organoplatínicos/farmacocinética , Ácido Oxônico/farmacocinética , Seleção de Pacientes , Farmacogenética , Medicina de Precisão , Pró-Fármacos/farmacocinética , Neoplasias Gástricas/genética , Neoplasias Gástricas/cirurgia , Tegafur/farmacocinética
20.
Invest New Drugs ; 32(5): 928-36, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24829073

RESUMO

PURPOSE: We aimed to investigate the recommended dose for the combination of TSU-68, a multiple-receptor tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor-2 and platelet-derived growth factor receptor-ß, and S-1, an oral fluoropyrimidine, in patients with advanced hepatocellular carcinoma (HCC) based on its associated dose-limiting toxicity (DLT) frequency. We also determined the safety, tolerability, pharmacokinetics (PK), and efficacy of the combination treatment. PATIENTS AND METHODS: Patients without any prior systemic therapy received 400 mg/day TSU-68 orally and 80 mg/day (level 1) or 100 mg/day (level 2) S-1 for 4 or 2 weeks followed by a 2- or 1-week rest period (groups A and B, respectively). According to the treatment, patients progressed from level 1B to level 2A, then level 2B. Safety and response rates were assessed. RESULTS: Eighteen patients were enrolled. Two patients at levels 1B and 2A but none at level 2B showed DLTs. The common adverse drug reactions were a decrease in hemoglobin levels, hypoalbuminemia, and anorexia, which were mild in severity (grades 1-2). PK data from levels 1B and 2A indicated that the area under the curve for TSU-68 and 5-fluorouracil was unlikely to be affected by the combination treatment. Response rate, disease control rate, median time to progression, and median overall survival were 27.8 %, 61.1 %, 5.3 months, and 12.8 months, respectively. CONCLUSION: The recommended dose for advanced HCC should be 400 mg/day TSU-68 and 100 mg/day S-1 for 4 weeks followed by 2-week rest.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/metabolismo , Administração Oral , Idoso , Idoso de 80 Anos ou mais , Inibidores da Angiogênese/administração & dosagem , Inibidores da Angiogênese/efeitos adversos , Inibidores da Angiogênese/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Combinação de Medicamentos , Feminino , Humanos , Indóis/administração & dosagem , Indóis/efeitos adversos , Indóis/farmacocinética , Masculino , Pessoa de Meia-Idade , Oxindóis , Ácido Oxônico/administração & dosagem , Ácido Oxônico/efeitos adversos , Ácido Oxônico/farmacocinética , Propionatos/administração & dosagem , Propionatos/efeitos adversos , Propionatos/farmacocinética , Pirróis , Tegafur/administração & dosagem , Tegafur/efeitos adversos , Tegafur/farmacocinética , Resultado do Tratamento
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