RESUMO
Dose adjustment based on renal function is essential in S-1, which contains the 5fluorouracil prodrug tegafur, and platinum-based agent oxaliplatin (SOX) combination chemotherapy for colorectal cancer in patients with chronic kidney disease. However, limited evidence on dose adjustment in acute kidney injury (AKI) and challenges in determining dosing strategies. This study investigated the pharmacokinetics of SOX chemotherapy and renal biomarkers in rats.AKI was prepared by renal ischaemia-reperfusion injury in 1,2-dimethylhydrazine-induced colorectal cancer model rats. Serum creatinine (sCr) levels were determined as a renal biomarker. After administration of S-1 (2 mg/kg tegafur) and oxaliplatin (5 mg/kg), drug concentrations of tegafur, 5-FU, and platinum were measured in the plasma and tumours.No alterations in the area under the plasma concentration-time curve (AUC0-24h) values of 5-fluorouracil were observed between control and AKI model rats. The tumour concentrations of 5-fluorouracil in the mild and severe AKI groups were significantly lower than control group. The AUC0-24h for platinum increased with AKI severity. Notably, population pharmacokinetic analysis identified sCr as a covariate in platinum distribution after SOX chemotherapy.To optimise dose adjustment of SOX chemotherapy in patients with AKI, sCr may be a key factor in determining the appropriate dose.
Assuntos
Injúria Renal Aguda , Neoplasias Colorretais , Humanos , Ratos , Animais , Oxaliplatina , Tegafur/toxicidade , Tegafur/farmacocinética , Fluoruracila/uso terapêutico , Fluoruracila/farmacocinética , Rim/patologia , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/tratamento farmacológico , Biomarcadores , Neoplasias Colorretais/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêuticoRESUMO
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 XenoenxertoRESUMO
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/farmacocinéticaRESUMO
Eye problems are an adverse reaction sometimes found in chemotherapy. Although not life-threatening, they can reduce patients' quality of life. The highest incidence of eye problems is reported for the combination anticancer drug S-1 (tegafur-gimeracil-oteracil), and methods to prevent or treat the eye problems caused by this drug are presently lacking. To determine early detection methods and treatment for adverse ocular reactions, we measured changes in tear volume and levels of tegafur (FT) and 5-fluorouracil (5-FU), an active metabolite of FT, in the tears of patients with long-term use of S-1. A total of 11 patients receiving S-1 monotherapy as adjuvant chemotherapy after gastric cancer surgery were included. Tear volume and FT and 5-FU levels in tears were measured by liquid chromatography with tandem mass spectrometry during a maximum of 8 treatment cycles (48 weeks). For analysis, patients were divided into two groups: "watering eyes" (n=6, complaints of watering eyes at least once during the treatment period) and "no watering eyes" (n=5, no complaints of watering eyes). Both groups exhibited increased FT and 5-FU levels in tears upon initiation of S-1 treatment, and levels rapidly decreased upon discontinuation. Our findings suggest a relationship between FT level in tears and tear volume in patients with long-term S-1 use. The symptom of watering eyes may thus be linked to FT level in tears.
Assuntos
Fluoruracila/farmacocinética , Ácido Oxônico/uso terapêutico , Lágrimas/química , Tegafur/farmacocinética , Administração Oral , Adulto , Idoso , Idoso de 80 Anos ou mais , Cromatografia Líquida , Combinação de Medicamentos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Ácido Oxônico/administração & dosagem , Qualidade de Vida , Espectrometria de Massas em Tandem , Tegafur/administração & dosagem , Tegafur/uso terapêuticoRESUMO
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 TerapêuticaRESUMO
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/farmacocinéticaRESUMO
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 TecidualRESUMO
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 TecidualRESUMO
Uracil-tegafur (UFT) is an oral anticancer drug containing uracil and 5fluorouracil prodrug tegafur and is widely used for adjuvant chemotherapy of colorectal cancer. Although clinical data show circadian variations in plasma 5fluorouracil concentrations during its long-term infusion, and feasibility studies of chronomodulated administration have been previously reported, the circadian pattern in plasma 5fluorouracil concentration after UFT administrations remains unclear. The aim of this study was to identify factors causing circadian variations in UFT pharmacokinetics and estimate circadian patterns of plasma 5fluorouracil concentration corresponding to UFT dosing time in rats. Rats were orally administered UFT (15â¯mg/kg as tegafur) at three different times of the day: 07:00 (23â¯h after light onset, HALO), 13:00 (5 HALO), or 19:00 (11 HALO), and then plasma concentrations of tegafur, 5fluorouracil, and uracil were measured after UFT administration. We found that the area under the plasma concentration-time curves (AUC0-∞) of 5fluorouracil depended on the UFT dosing time of day with a 2.4-fold difference between the peak (at 19:00: 13.7⯱â¯1.4⯵mol·h/L) and trough (at 13:00: 5.6⯱â¯1.3⯵mol·h/L). The simulated population mean clearance of 5fluorouracil followed a 24-h cosine circadian curve, with the highest value in the early light phase being 2.2-fold higher than the lowest value in the early dark phase, which was an inverse circadian pattern compared to the plasma 5fluorouracil concentration. The plasma tegafur levels suggested that circadian variation in tegafur absorption and conversion to 5fluorouracil are factors causing variations in plasma 5fluorouracil levels following UFT administration. In conclusion, the circadian pattern of 5fluorouracil clearance and circadian variations in tegafur pharmacokinetics are important determinants of plasma 5fluorouracil concentrations following UFT administration. This knowledge could help in developing a chronomodulated administration strategy of UFT for improving clinical outcomes.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Ritmo Circadiano , Tegafur/administração & dosagem , Tegafur/farmacocinética , Uracila/administração & dosagem , Uracila/farmacocinética , Administração Oral , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/sangue , Biotransformação , Esquema de Medicação , Cronofarmacoterapia , Combinação de Medicamentos , Masculino , Modelos Biológicos , Ratos Wistar , Tegafur/análogos & derivados , Tegafur/sangue , Uracila/análogos & derivados , Uracila/sangueRESUMO
PURPOSE: To establish a method for the measurement of 5-fluorouracil (5-FU), and tegafur (FT) in tear samples from patients treated with oral fluoropyrimidine anticancer agent S-1. STUDY DESIGN: Cross-sectional study. METHODS: High performance liquid chromatographic (HPLC) method reported for plasma samples was modified for tear samples. Simulated-tear solutions containing lactoferrin, lysozyme and standard solution containing 5-FU or FT were prepared for preliminary measurements. Tear samples from seven patients treated with S-1 were included. The tears were collected following S-1 administration using Schirmer's strips. RESULTS: 5-FU and FT concentrations of pure standard solution without extraction process were detected as original concentration. However, on extraction, FT samples in simulated-tear solution showed a peak for 5-FU but not for FT. FT was converted to 5-FU in the extraction process. Decomposition from FT to 5-FU was suppressed when 50 mg/mL bovine serum albumin was added during extraction. The mean concentrations of 5-FU and FT in tears during S-1 treatment were 0.17 ± 0.11 and 1.94 ± 0.71 µg/mL, respectively. CONCLUSION: A simple HPLC method to determine 5-FU and FT in tear samples was established.
Assuntos
Fluoruracila/farmacocinética , Neoplasias/tratamento farmacológico , Ácido Oxônico/administração & dosagem , Lágrimas/química , Tegafur/farmacocinética , Administração Oral , Adulto , Idoso , Idoso de 80 Anos ou mais , Antimetabólitos Antineoplásicos/administração & dosagem , Cromatografia Líquida de Alta Pressão , Estudos Transversais , Combinação de Medicamentos , Quimioterapia Combinada , Feminino , Humanos , Imunossupressores/farmacocinética , Masculino , Pessoa de Meia-Idade , Neoplasias/metabolismo , Tegafur/administração & dosagemRESUMO
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 , GencitabinaRESUMO
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 TratamentoRESUMO
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/químicaRESUMO
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 TratamentoRESUMO
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 NeoplasiasRESUMO
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/farmacocinéticaRESUMO
The aim of the present study was to investigate the potential application of (+)-camphor as a penetration enhancer for the transdermal delivery of drugs with differing lipophilicity. The skin irritation of camphor was evaluated by in vitro cytotoxicity assays and in vivo transdermal water loss (TEWL) measurements. A series of model drugs with a wide span of lipophilicity (logP value ranging from 3.80 to -0.95), namely indometacin, lidocaine, aspirin, antipyrine, tegafur and 5-fluorouracil, were tested using in vitro transdermal permeation experiments to assess the penetration-enhancing profile of camphor. Meanwhile, the in vivo skin microdialysis was carried out to further investigate the enhancing effect of camphor on the lipophilic and hydrophilic model drugs (i.e. lidocaine and tegafur). SC (stratum corneum)/vehicle partition coefficient and Fourier transform infrared spectroscopy (FTIR) were performed to probe the regulation action of camphor in the skin permeability barrier. It was found that camphor produced a relatively low skin irritation, compared with the frequently-used and standard penetration enhancer laurocapram. In vitro skin permeation studies showed that camphor could significantly facilitate the transdermal absorption of model drugs with differing lipophilicity, and the penetration-enhancing activities were in a parabola curve going downwards with the drug logP values, which displayed the optimal penetration-enhancing efficiency for the weak lipophilic or hydrophilic drugs (an estimated logP value of 0). In vivo skin microdialysis showed that camphor had a similar penetration behavior on transdermal absorption of model drugs. Meanwhile, the partition of lipophilic drugs into SC was increased after treatment with camphor, and camphor also produced a shift of CH2 vibration of SC lipid to higher wavenumbers and decreased the peak area of the CH2 vibration, probably resulting in the alteration of the skin permeability barrier. This suggests that camphor might be a safe and effective penetration enhancer for transdermal drug delivery.
Assuntos
Cânfora/farmacologia , Interações Hidrofóbicas e Hidrofílicas , Lidocaína/farmacocinética , Preparações Farmacêuticas/metabolismo , Absorção Cutânea/efeitos dos fármacos , Pele/efeitos dos fármacos , Tegafur/farmacocinética , Administração Cutânea , Animais , Cânfora/administração & dosagem , Cânfora/efeitos adversos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Ratos , Pele/metabolismoRESUMO
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 TecidualRESUMO
BACKGROUND: The best-known cause of intolerance to fluoropyrimidines is dihydropyrimidine dehydrogenase (DPD) deficiency, which can result from deleterious polymorphisms in the gene encoding DPD (DPYD), including DPYD*2A and c.2846A>T. Three other variants-DPYD c.1679T>G, c.1236G>A/HapB3, and c.1601G>A-have been associated with DPD deficiency, but no definitive evidence for the clinical validity of these variants is available. The primary objective of this systematic review and meta-analysis was to assess the clinical validity of c.1679T>G, c.1236G>A/HapB3, and c.1601G>A as predictors of severe fluoropyrimidine-associated toxicity. METHODS: We did a systematic review of the literature published before Dec 17, 2014, to identify cohort studies investigating associations between DPYD c.1679T>G, c.1236G>A/HapB3, and c.1601G>A and severe (grade ≥3) fluoropyrimidine-associated toxicity in patients treated with fluoropyrimidines (fluorouracil, capecitabine, or tegafur-uracil as single agents, in combination with other anticancer drugs, or with radiotherapy). Individual patient data were retrieved and analysed in a multivariable analysis to obtain an adjusted relative risk (RR). Effect estimates were pooled by use of a random-effects meta-analysis. The threshold for significance was set at a p value of less than 0·0167 (Bonferroni correction). FINDINGS: 7365 patients from eight studies were included in the meta-analysis. DPYD c.1679T>G was significantly associated with fluoropyrimidine-associated toxicity (adjusted RR 4·40, 95% CI 2·08-9·30, p<0·0001), as was c.1236G>A/HapB3 (1·59, 1·29-1·97, p<0·0001). The association between c.1601G>A and fluoropyrimidine-associated toxicity was not significant (adjusted RR 1·52, 95% CI 0·86-2·70, p=0·15). Analysis of individual types of toxicity showed consistent associations of c.1679T>G and c.1236G>A/HapB3 with gastrointestinal toxicity (adjusted RR 5·72, 95% CI 1·40-23·33, p=0·015; and 2·04, 1·49-2·78, p<0·0001, respectively) and haematological toxicity (adjusted RR 9·76, 95% CI 3·03-31·48, p=0·00014; and 2·07, 1·17-3·68, p=0·013, respectively), but not with hand-foot syndrome. DPYD*2A and c.2846A>T were also significantly associated with severe fluoropyrimidine-associated toxicity (adjusted RR 2·85, 95% CI 1·75-4·62, p<0·0001; and 3·02, 2·22-4·10, p<0·0001, respectively). INTERPRETATION: DPYD variants c.1679T>G and c.1236G>A/HapB3 are clinically relevant predictors of fluoropyrimidine-associated toxicity. Upfront screening for these variants, in addition to the established variants DPYD*2A and c.2846A>T, is recommended to improve the safety of patients with cancer treated with fluoropyrimidines. FUNDING: None.
Assuntos
Antimetabólitos Antineoplásicos/efeitos adversos , Antimetabólitos Antineoplásicos/farmacocinética , Di-Hidrouracila Desidrogenase (NADP)/genética , Gastroenteropatias/genética , Doenças Hematológicas/genética , Neoplasias/tratamento farmacológico , Polimorfismo Genético , Capecitabina/efeitos adversos , Capecitabina/farmacocinética , Di-Hidrouracila Desidrogenase (NADP)/metabolismo , Fluoruracila/efeitos adversos , Fluoruracila/farmacocinética , Gastroenteropatias/induzido quimicamente , Gastroenteropatias/diagnóstico , Predisposição Genética para Doença , Doenças Hematológicas/induzido quimicamente , Doenças Hematológicas/diagnóstico , Humanos , Análise Multivariada , Neoplasias/diagnóstico , Neoplasias/genética , Razão de Chances , Farmacogenética , Fenótipo , Medição de Risco , Fatores de Risco , Índice de Gravidade de Doença , Tegafur/efeitos adversos , Tegafur/farmacocinéticaRESUMO
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.