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1.
Clin Pharmacokinet ; 63(7): 1037-1044, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38951433

RESUMEN

BACKGROUND AND OBJECTIVES: Trifluridine/tipiracil, registered for the treatment of patients with metastatic gastric and colorectal cancer, is a substrate and inhibitor for the organic cation transporter 2 (OCT2) and the multidrug and toxin extrusion protein 1 (MATE1), which raises the potential for drug-drug interactions with other OCT2/MATE1 modulators. Therefore, we prospectively examined the effect of an OCT2/MATE1 inhibitor (cimetidine) and substrate (metformin) on the pharmacokinetics of trifluridine. METHODS: In this three-phase crossover study, patients with metastatic colorectal or gastric cancer were sequentially treated with trifluridine/tipiracil alone (phase A), trifluridine/tipiracil concomitant with metformin (phase B) and trifluridine/tipiracil concomitant with cimetidine (phase C). The primary endpoint was the relative difference in exposure of trifluridine assessed by the area under the curve from timepoint zero to infinity. A > 30% change in exposure was considered clinically relevant. A p-value of < 0.025 was considered significant because of a Bonferroni correction. RESULTS: Eighteen patients were included in the analysis. Metformin did not significantly alter the exposure to trifluridine (- 12.6%; 97.5% confidence interval - 25.0, 1.8; p = 0.045). Cimetidine did alter the exposure to trifluridine significantly (+ 18.0%; 97.5% confidence interval 4.5, 33.3; p = 0.004), but this increase did not meet our threshold for clinical relevance. Metformin trough concentrations were not influenced by trifluridine/tipiracil. CONCLUSIONS: Our result suggests that the OCT2/MATE1 modulators cimetidine and metformin can be co-administered with trifluridine/tipiracil without clinically relevant effects on drug exposure. CLINICAL TRIAL REGISTRATION: NL8067 (registered 04-10-2019).


Asunto(s)
Cimetidina , Estudios Cruzados , Interacciones Farmacológicas , Metformina , Proteínas de Transporte de Catión Orgánico , Trifluridina , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Cimetidina/farmacocinética , Cimetidina/farmacología , Cimetidina/administración & dosificación , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/metabolismo , Combinación de Medicamentos , Metformina/farmacocinética , Metformina/administración & dosificación , Metformina/farmacología , Proteínas de Transporte de Catión Orgánico/metabolismo , Proteínas de Transporte de Catión Orgánico/antagonistas & inhibidores , Transportador 2 de Cátion Orgánico/metabolismo , Estudios Prospectivos , Pirrolidinas/farmacocinética , Pirrolidinas/administración & dosificación , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/metabolismo , Timina , Trifluridina/farmacocinética , Trifluridina/administración & dosificación
2.
Cancer Chemother Pharmacol ; 91(2): 167-177, 2023 02.
Artículo en Inglés | MEDLINE | ID: mdl-36622402

RESUMEN

PURPOSE: Colorectal cancer (CRC) is the second most common cause of cancer death worldwide. Trifluridine (FTD) remained at higher concentrations longer when administered along with tipiracil (TPI) compared with FTD alone. Lonsurf® is a combination formulation consisting of FTD and TPI. This study aimed to investigate the bioequivalence of FTD/TPI formulations in Chinese metastatic colorectal cancer (mCRC) patients. METHODS: In this phase I, randomized, open-label, single-dose, two-sequence, four-cycle crossover study in mCRC patients, the bioequivalence of 60 mg (20 mg tablet, 3 tablets) of the test formulation and the reference formulation (Lonsurf®) was evaluated. Due to its high variability, the method of reference-scaled average bioequivalence (RSABE) was used to investigate the bioequivalence of the test and reference formulations. RESULTS: Thirty-two patients were enrolled. 78.1% of the subjects were male, and the mean (standard deviation) age was 53.9 (SD = ± 9.0) years old. The time to reach the maximum plasma concentration (Tmax) was almost 2.0 h post-dose. The geometric least-squares mean ratios (GMRs) (test/reference) of Cmax and AUC0-t for FTD were 95.3% and 102.9%, respectively, with 90% confidence intervals (CIs) for the natural log-transformed ratios of Cmax and AUC0-t of 90.0-100.9% and 99.9-105.9%, while the GMRs of Cmax and AUC0-t for TPI were 95.7% and 100.7%, respectively, with 90% CIs of 90.5-101.2% and 97.0-104.7%. In addition, the GMRs of Cmax and AUC0-t for FTD's major metabolite, trifluorothymine (FTY), were 94.8 (90% CI 90.3-99.5%) and 99.33 (90% CI 96.9-101.9%), respectively. These were in accord with the FDA bioequivalence definition interval of 80-125%. CONCLUSION: The test and reference FTD/TPI formulations were bioequivalent in Chinese mCRC patients under fed conditions.


Asunto(s)
Neoplasias Colorrectales , Trifluridina , Femenino , Humanos , Masculino , Persona de Mediana Edad , Área Bajo la Curva , Neoplasias Colorrectales/tratamiento farmacológico , Estudios Cruzados , Pueblos del Este de Asia , Comprimidos , Equivalencia Terapéutica , Trifluridina/farmacocinética , Combinación de Medicamentos , Adulto
3.
Cancer Chemother Pharmacol ; 88(3): 485-497, 2021 09.
Artículo en Inglés | MEDLINE | ID: mdl-34097100

RESUMEN

PURPOSE: Trifluridine/tipiracil (FTD/TPI) is approved for advanced colorectal and gastric/gastroesophageal cancer; however, data in patients with renal impairment (RI) are limited. This phase I study evaluated FTD/TPI in patients with advanced solid tumors and varying degrees of RI to develop dosing guidance. METHODS: Patients were enrolled into normal renal function (CrCl ≥ 90 mL/min), mild RI (CrCl 60-89 mL/min), or moderate RI (CrCl 30-59 mL/min) cohorts and administered the recommended FTD/TPI dose (35 mg/m2 twice daily, days 1-5 and 8-12; 28-day cycle). Based on interim pharmacokinetics/safety data, patients with severe RI (CrCl 15-29 mL/min) were enrolled and received FTD/TPI 20 mg/m2 twice daily. RESULTS: Forty-three patients (normal renal function [n = 12]; mild RI [n = 12]; moderate RI [n = 11]; severe RI [n = 8]) were enrolled and treated. At steady state, compared to values in patients with normal renal function, FTD area under the curve (AUC) was not significantly different in patients with RI, but TPI AUC was significantly higher and increased with RI severity. FTD/TPI safety profile was consistent with prior experience, but grade ≥ 3 adverse events (AEs) were more frequent in the RI cohorts (83.3% [mild], 90.9% [moderate], 75.0% [severe], and normal [50.0%]). Hematologic AEs (anemia and neutropenia) were more frequent with RI. Overall, seven patients discontinued because of unrelated, nonhematologic AEs. CONCLUSION: FTD/TPI is safe and tolerable at the recommended 35 mg/m2 dose in patients with mild/moderate RI and at the reduced 20 mg/m2 dose in patients with severe RI. TRIAL REGISTRATION: NCT02301117, registration date: November 21, 2014.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Enfermedades Renales/fisiopatología , Neoplasias/tratamiento farmacológico , Pirrolidinas/administración & dosificación , Timina/administración & dosificación , Trifluridina/administración & dosificación , Adulto , Anciano , Anciano de 80 o más Años , Anemia/inducido químicamente , Anemia/epidemiología , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Área Bajo la Curva , Estudios de Cohortes , Combinación de Medicamentos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neutropenia/inducido químicamente , Neutropenia/epidemiología , Pirrolidinas/efectos adversos , Pirrolidinas/farmacocinética , Índice de Severidad de la Enfermedad , Timina/efectos adversos , Timina/farmacocinética , Trifluridina/efectos adversos , Trifluridina/farmacocinética
4.
Cancer Chemother Pharmacol ; 88(3): 393-402, 2021 09.
Artículo en Inglés | MEDLINE | ID: mdl-34028598

RESUMEN

PURPOSE: The current study aimed to determine the efficacy of trifluridine/tipiracil for elderly patients with advanced colorectal cancer. METHODS: This single-arm, open-label, multicenter, phase II study included elderly patients aged 65 years or more who had fluoropyrimidine-refractory advanced colorectal cancer and received trifluridine/tipiracil (70 mg/m2, days 1-5 and 8-12, every 4 weeks). The primary endpoint was progression-free survival (PFS), while secondary endpoints included overall survival (OS), overall response rate (ORR), toxicities, association between efficacy and geriatric assessment scores, and association between toxicity and plasma drug concentrations. RESULTS: A total of 30 patients with a mean age of 73 years were enrolled. Median PFS was 2.3 months (95% confidence interval, 1.9-4.3 months), while median OS was 5.7 months (95% confidence interval, 3.7-8.9 months). Patients had an ORR of 0%, with 57% having stable disease. Grade 4 neutropenia was observed in 13% of the patients. Patients with a higher G8 score (15 or more) showed longer PFS than those with a lower G8 score (median 4.6 vs. 2.0 months; p = 0.047). Moreover, patients with grade 3 or 4 neutropenia showed higher maximum trifluridine concentrations than those with grade 1 or 2 neutropenia (mean 2945 vs. 2107 ng/mL; p = 0.036). DISCUSSION: The current phase II trial demonstrated that trifluridine/tipiracil was an effective and well-tolerated option for elderly patients with advanced colorectal cancer. Moreover, geriatric assessment tools and/or plasma drug concentration monitoring might be helpful in predicting the efficacy and toxicities in elderly patients receiving this drug. TRIAL REGISTRATION NUMBER: UMIN000017589, 15/May/2015 (The University Hospital Medical Information Network).


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Neoplasias Colorrectales/tratamiento farmacológico , Evaluación Geriátrica/métodos , Pirrolidinas/administración & dosificación , Timina/administración & dosificación , Trifluridina/administración & dosificación , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Biomarcadores de Tumor/metabolismo , Combinación de Medicamentos , Monitoreo de Drogas/métodos , Femenino , Humanos , Masculino , Neutropenia/inducido químicamente , Supervivencia sin Progresión , Pirrolidinas/efectos adversos , Pirrolidinas/farmacocinética , Tasa de Supervivencia , Timina/efectos adversos , Timina/farmacocinética , Trifluridina/efectos adversos , Trifluridina/farmacocinética
5.
Br J Clin Pharmacol ; 85(6): 1239-1246, 2019 06.
Artículo en Inglés | MEDLINE | ID: mdl-30628113

RESUMEN

AIMS: Trifluridine/tipiracil (FTD/TPI) prolongs survival in refractory metastatic colorectal cancer, but limited data exist on its use in patients with hepatic impairment. This Phase I, open-label, nonrandomized study investigated the safety, tolerability and pharmacokinetics of FTD/TPI in patients with advanced solid tumours (except breast cancer) and varying degrees of hepatic impairment, to provide dosing recommendations. METHODS: Patients aged ≥18 years with advanced solid tumours and normal hepatic function, or mild, moderate or severe hepatic impairment according to National Cancer Institute criteria, were planned to be enrolled. Patients received FTD/TPI 35 mg/m2 orally twice daily on days 1-5 and 8-12 of each 28-day cycle. RESULTS: Twenty-four patients were enrolled to the normal hepatic function (n = 8) and mild (n = 10) and moderate (n = 6) hepatic impairment cohorts. Overall, 12 patients (50.0%) had at least 1 adverse event leading to study discontinuation. In the moderate hepatic impairment cohort, 5 of 6 patients experienced grade ≥ 3 elevation in bilirubin. No patients with severe hepatic impairment were enrolled. FTD area under the curve at steady state decreased by 18% and 22% in the mild and moderate cohorts, respectively; however, no clear change was observed in TPI area under the curve. CONCLUSIONS: FTD/TPI can be safely administered in patients with normal hepatic function and mild hepatic impairment, with no initial dose adjustment. FTD/TPI is not recommended for use in patients with moderate hepatic impairment because of findings of grade 3 or 4 increased blood bilirubin. Therefore, FTD/TPI is not recommended for patients with moderate or severe hepatic impairment.


Asunto(s)
Antineoplásicos/farmacocinética , Hepatopatías/complicaciones , Hígado/metabolismo , Neoplasias/tratamiento farmacológico , Pirrolidinas/farmacocinética , Trifluridina/farmacocinética , Uracilo/análogos & derivados , Administración Oral , Adulto , Anciano , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Bilirrubina/sangre , Esquema de Medicación , Combinación de Medicamentos , Cálculo de Dosificación de Drogas , Femenino , Humanos , Hepatopatías/diagnóstico , Hepatopatías/metabolismo , Masculino , Persona de Mediana Edad , Modelos Biológicos , Neoplasias/complicaciones , Neoplasias/diagnóstico , Pirrolidinas/administración & dosificación , Pirrolidinas/efectos adversos , Índice de Severidad de la Enfermedad , Timina , Resultado del Tratamiento , Trifluridina/administración & dosificación , Trifluridina/efectos adversos , Estados Unidos , Uracilo/administración & dosificación , Uracilo/efectos adversos , Uracilo/farmacocinética
6.
Anticancer Res ; 38(3): 1427-1434, 2018 03.
Artículo en Inglés | MEDLINE | ID: mdl-29491068

RESUMEN

BACKGROUND/AIM: Trifluridine/tipiracil (FTD/TPI) is used for metastatic colorectal cancer, that is refractory to 5-fluorouracil (5-FU)-based therapies. However, the impact of pre-exposure to 5-FU on the anti-cancer effect of FTD, which is a key component of FTD/TPI, is unclear. MATERIALS AND METHODS: The incorporation into DNA and anti-cancer activity of FTD were analyzed in several cancer cell lines under response to FTD treatment with or without 5-FU pre-exposure. The volumes of tumors in xenografted nude mice were examined among groups that were either untreated or treated with S-1, FTD/TPI or FTD/TPI with pre-exposure to S-1. RESULTS: Pre-exposure to 5-FU significantly increased FTD incorporation into DNA and enhanced its anti-cancer effect for viability and proliferation of cancer cells. In the xenograft nude mouse model, the tumor volumes in the FTD/TPI-treated and S-1-pre-exposed group were lower than those in the FTD/TPI-only-treated group. Although both FTD dose and exposure time in the FTD/TPI-treated and S-1-pre-exposed mice were smaller than those in the FTD/TPI-only-treated mice, the incorporated FTD in the tumors in the former group was 86.5% of that in the latter group. CONCLUSION: Pre-exposure to 5-FU enhanced the incorporation into DNA and the anti-cancer effect of FTD in the context of colorectal cancer. Our data indicate the potential for a new sequential therapy using S-1 and FTD/TPI to improve prognosis of colorectal cancer.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Neoplasias del Colon/tratamiento farmacológico , Fluorouracilo/farmacología , Trifluridina/farmacología , Ensayos Antitumor por Modelo de Xenoinjerto , Animales , Antimetabolitos Antineoplásicos/administración & dosificación , Antimetabolitos Antineoplásicos/farmacología , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Neoplasias del Colon/patología , ADN de Neoplasias/genética , ADN de Neoplasias/metabolismo , Combinación de Medicamentos , Fluorouracilo/administración & dosificación , Humanos , Masculino , Ratones Endogámicos BALB C , Ratones Desnudos , Ácido Oxónico/administración & dosificación , Ácido Oxónico/farmacología , Pronóstico , Tegafur/administración & dosificación , Tegafur/farmacología , Trifluridina/administración & dosificación , Trifluridina/farmacocinética
7.
Biopharm Drug Dispos ; 39(1): 38-46, 2018 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-29055025

RESUMEN

Trifluridine (FTD) exhibits anticancer activities after its oral administration despite its hydrophilic nature. It was previously reported that concentrative nucleoside transporter (CNT) 1 mediates the apical uptake of FTD in human small intestinal epithelial cells (HIECs). In the present study, FTD was also identified as a substrate for equilibrative nucleoside transporter (ENT) 1 and ENT2 in transporter gene-transfected cells. An immunocytochemical analysis revealed that ENT1 was expressed at the basolateral and apical membranes of HIECs. Cellular accumulation increased in the presence of S-(4-nitrobenzyl)-6-thioinosine (NBMPR), an ENT selective inhibitor. Cytotoxicity in HIEC monolayers at low FTD concentrations was increased by NBMPR, and this may have been due to inhibition of the ENT-mediated basolateral transport of FTD by NBMPR. These results suggest that ENTs reduce the intestinal cytotoxicity of FTD by facilitating its basolateral efflux. On the other hand, the intracellular accumulation and cytotoxicity of FTD in HIECs were decreased at higher concentrations of FTD by NBMPR, and this may have been due to the NBMPR inhibition of the apical uptake of FTD, which has been suggested to be mediated by CNTs and ENTs. In conclusion, ENTs were responsible for intestinal transepithelial permeation by mediating the basolateral efflux of FTD after its uptake by CNT1 from the apical side, resulting in decreases in its intracellular accumulation and intestinal toxicity in humans. Equilibrative nucleoside transporters may also partially contribute to the low-affinity uptake of FTD across the apical membrane along with high-affinity CNT1.


Asunto(s)
Tranportador Equilibrativo 1 de Nucleósido/metabolismo , Transportador Equilibrativo 2 de Nucleósido/metabolismo , Intestino Delgado/metabolismo , Trifluridina/farmacocinética , Transporte Biológico , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Interacciones Farmacológicas , Células Epiteliales/metabolismo , Humanos , Intestino Delgado/efectos de los fármacos , Tioinosina/análogos & derivados , Tioinosina/farmacología , Trifluridina/farmacología
8.
Sci Rep ; 7(1): 16969, 2017 12 05.
Artículo en Inglés | MEDLINE | ID: mdl-29208954

RESUMEN

Trifluridine/tipiracil (TFTD, TAS-102) is an orally administrated anti-cancer drug with efficacy validated for patients with metastatic colorectal cancer (mCRC). Trifluridine (FTD) is an active cytotoxic component of TFTD and mediates the anticancer effect via its incorporation into DNA. However, it has not been examined whether FTD is incorporated into the tissues of patients who received TFTD medication. By detecting FTD incorporation into DNA by a specific antibody, we successfully detected FTD in the bone marrow and spleen cells isolated from FTD-challenged mice as well as human peripheral blood mononuclear cells (PBMCs) activated with phytohemagglutinin-P and exposed to FTD in vitro. FTD was also detected in PBMCs isolated from mCRC patients who had administrated TFTD medication. Intriguingly, weekly evaluation of PBMCs from mCRC patients revealed the percentage of FTD-positive PBMCs increased and decreased in parallel with the administration and cessation of TFTD medication, respectively. To our knowledge, this is the first report to detect an active cytotoxic component of a chemotherapeutic drug in clinical specimens using a specific antibody. This technique may enable us to predict the clinical benefits or the adverse effects of TFTD in mCRC patients.


Asunto(s)
Neoplasias Colorrectales/tratamiento farmacológico , Leucocitos Mononucleares/efectos de los fármacos , Trifluridina/sangre , Administración Oral , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/sangre , Antineoplásicos/farmacocinética , Células de la Médula Ósea/efectos de los fármacos , Neoplasias Colorrectales/sangre , Neoplasias Colorrectales/patología , ADN/metabolismo , Combinación de Medicamentos , Células HCT116 , Humanos , Leucocitos Mononucleares/metabolismo , Masculino , Ratones Endogámicos BALB C , Fitohemaglutininas/farmacología , Pirrolidinas , Bazo/efectos de los fármacos , Bazo/metabolismo , Timina , Trifluridina/administración & dosificación , Trifluridina/farmacocinética , Uracilo/análogos & derivados , Ensayos Antitumor por Modelo de Xenoinjerto
9.
Eur J Cancer ; 86: 197-206, 2017 11.
Artículo en Inglés | MEDLINE | ID: mdl-28992563

RESUMEN

BACKGROUND: Trifluridine (FTD) is an active cytotoxic component of the metastatic colorectal cancer (mCRC) drug TAS-102, and thymidine phosphorylase inhibitor (TPI) inhibits the rapid degradation of FTD. We tested whether single nucleotide polymorphisms (SNPs) in genes involved in FTD metabolism and TPI excretion could predict outcome in patients with mCRC treated with TAS-102. PATIENTS AND METHODS: We investigated three different cohorts: a training cohort (n = 52) and a testing cohort (n = 129) both receiving TAS-102 and a control cohort (n = 52) receiving regorafenib. SNPs of TK1, ENT1, CNT1, MATE1, MATE2 and OCT2 were analysed by polymerase chain reaction-based direct DNA sequencing. RESULTS: In the training cohort, patients with any ENT1 rs760370 G allele had a significantly longer progression-free survival (PFS; 3.5 versus 2.1 months, respectively, hazard ratio [HR] 0.44, P = 0.004) and overall survival (OS; 8.7 versus 5.3 months, respectively, HR 0.27, P = 0.003) than the A/A genotype. These findings were validated in the testing cohort (P = 0.021 and 0.009 for PFS and OS, respectively). In addition, the combination of ENT1 rs760370, MATE1 rs2289669 and OCT2 rs316019 SNPs significantly stratified patients with the risk of PFS and OS in both cohorts (P < 0.001 for PFS and OS in the training cohort; P = 0.053 and 0.025 for PFS and OS, respectively, in the testing cohort). No significant differences were observed in the control group. CONCLUSIONS: The combination of ENT1, MATE1 and OCT2 SNPs may serve as a predictive and prognostic marker in mCRC patients treated with TAS-102.


Asunto(s)
Antineoplásicos/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Tranportador Equilibrativo 1 de Nucleósido/genética , Proteínas de Transporte de Catión Orgánico/genética , Transportador 2 de Cátion Orgánico/genética , Variantes Farmacogenómicas , Polimorfismo de Nucleótido Simple , Trifluridina/uso terapéutico , Uracilo/análogos & derivados , Antineoplásicos/efectos adversos , Antineoplásicos/farmacocinética , California , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Supervivencia sin Enfermedad , Combinación de Medicamentos , Tranportador Equilibrativo 1 de Nucleósido/metabolismo , Femenino , Frecuencia de los Genes , Genotipo , Humanos , Italia , Japón , Masculino , Metástasis de la Neoplasia , Proteínas de Transporte de Catión Orgánico/metabolismo , Transportador 2 de Cátion Orgánico/metabolismo , Farmacogenética , Pruebas de Farmacogenómica , Fenotipo , Valor Predictivo de las Pruebas , Pirrolidinas , Estudios Retrospectivos , Timina , Resultado del Tratamiento , Trifluridina/efectos adversos , Trifluridina/farmacocinética , Uracilo/efectos adversos , Uracilo/farmacocinética , Uracilo/uso terapéutico
10.
J Clin Pharmacol ; 57(6): 751-759, 2017 06.
Artículo en Inglés | MEDLINE | ID: mdl-28070894

RESUMEN

TAS-102 (trifluridine/tipiracil) is composed of an antineoplastic thymidine-based nucleoside analogue trifluridine (FTD), and a thymidine phosphorylase inhibitor, tipiracil (TPI), at a molar ratio of 1:0.5 (weight ratio, 1:0.471). A phase 1 study evaluated relative bioavailability of TAS-102 tablets compared with an oral solution containing equivalent amounts of FTD and TPI. In an open-label, 2-sequence, 3-period, crossover bioavailability study (part 1), patients 18 years or older with advanced solid tumors were randomized to receive TAS-102 tablets (60 mg; 3 × 20-mg tablets) on day 1 and TAS-102 oral solution (60 mg) on days 8 and 15, or the opposite sequence. In an extension (part 2), all patients received TAS-102 tablets. Of the 46 patients treated in the crossover study, 38 were evaluable in the crossover bioavailability pharmacokinetic population. For area under the concentration-time curve (AUC)0-∞ and AUC0-last for FTD and TPI, and maximum plasma concentration (Cmax ) for TPI, the 90% confidence intervals (CIs) of the geometric mean ratios were within the 0.80 to 1.25 boundary for demonstration of bioequivalence; for FTD Cmax , the lower limit of the 90%CI was 0.786. The most frequently reported treatment-related grade 3 or 4 adverse events were neutropenia (7 patients) and decreased neutrophil count (3 patients). Although the lower limit of the 90%CI for the geometric mean ratio of FTD Cmax was slightly lower than 0.80, the bioavailability of the TAS-102 tablet is considered clinically similar to that of a TAS-102 oral solution. TAS-102 was well tolerated in this population of patients with advanced solid tumors.


Asunto(s)
Antineoplásicos/farmacocinética , Neoplasias/metabolismo , Trifluridina/farmacocinética , Uracilo/análogos & derivados , Administración Oral , Anciano , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Antineoplásicos/uso terapéutico , Disponibilidad Biológica , Estudios Cruzados , Combinación de Medicamentos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neoplasias/sangre , Neoplasias/tratamiento farmacológico , Pirrolidinas , Soluciones , Comprimidos , Timina , Resultado del Tratamiento , Trifluridina/administración & dosificación , Trifluridina/efectos adversos , Trifluridina/uso terapéutico , Uracilo/administración & dosificación , Uracilo/efectos adversos , Uracilo/farmacocinética , Uracilo/uso terapéutico
11.
Invest New Drugs ; 35(2): 189-197, 2017 04.
Artículo en Inglés | MEDLINE | ID: mdl-28111727

RESUMEN

Background Trifluridine, a thymidine-based chemotherapeutic, has limited bioavailability after clinical administration as it is rapidly degraded via thymidine phosphorylase. An oral combination tablet combines trifluridine with a potent thymidine phosphorylase inhibitor, tipiracil hydrochloride. This study's objective was to evaluate whether trifluridine/tipiracil (TAS-102) administration increases trifluridine exposure vs trifluridine alone. Methods This open-label pharmacokinetic study randomly assigned patients with advanced solid tumors into two groups. On the morning of day 1, one group received a single 35 mg/m2 dose of trifluridine/tipiracil and the other group received a single 35-mg/m2 dose of trifluridine. Both groups received trifluridine/tipiracil 35 mg/m2 on the evening of day 1, then twice daily on days 2-5 and 8-12 in a 28-day cycle. Results Twenty patients received an initial one-time dose of trifluridine alone and 19 other patients received an initial dose of trifluridine/tipiracil. Trifluridine area under the curve (AUC0-last) and maximum observed plasma concentrations (Cmax) were approximately 37- and 22-fold higher, respectively, with trifluridine/tipiracil vs trifluridine alone. Plasma concentrations of the major metabolite of trifluridine were lower following the administration of trifluridine/tipiracil vs trifluridine alone. Conclusion Tipiracil administered in combination with trifluridine significantly increased exposure to trifluridine compared with trifluridine alone.


Asunto(s)
Antineoplásicos/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Neoplasias/tratamiento farmacológico , Pirrolidinas/farmacocinética , Timina/farmacocinética , Trifluridina/farmacocinética , Anciano , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Interacciones Farmacológicas , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neoplasias/metabolismo , Pirrolidinas/administración & dosificación , Pirrolidinas/efectos adversos , Pirrolidinas/uso terapéutico , Timina/administración & dosificación , Timina/efectos adversos , Timina/uso terapéutico , Resultado del Tratamiento , Trifluridina/administración & dosificación , Trifluridina/efectos adversos , Trifluridina/uso terapéutico
12.
Clin Adv Hematol Oncol ; 14(8): 630-8, 2016 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-27487107

RESUMEN

Colorectal cancer (CRC) is the second leading cause of cancer-related death in the United States. Approximately 20% of patients have metastatic disease at diagnosis, and a vast number of these patients die within 5 years. The advent of modern chemotherapeutics has improved median overall survival for these patients; nonetheless, we must keep striving for better outcomes. Trifluridine/tipiracil (TAS-102) and regorafenib are agents newly approved by the US Food and Drug Administration that show promise in the treatment of metastatic colorectal cancer. These drugs have the benefit of being formulated for oral administration and have different side effect profiles. These differences are important in the selection of the best therapy for each patient, especially if the patient is prone to a side effect that is unique to just one of the treatments. In this review, we discuss the mechanism of action, side effect profile, and clinical efficacy of trifluridine/tipiracil, and compare them with those of regorafenib. Future trials will evaluate the use of these drugs in earlier lines of therapy, alone and in combination with other agents. We now have 2 more agents in the arsenal against metastatic colorectal cancer and the future is looking brighter for patients, although we still have a long way to go.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Ensayos Clínicos como Asunto , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/mortalidad , Humanos , Metástasis de la Neoplasia , Compuestos de Fenilurea/administración & dosificación , Compuestos de Fenilurea/farmacocinética , Piridinas/administración & dosificación , Piridinas/farmacocinética , Resultado del Tratamiento , Trifluridina/administración & dosificación , Trifluridina/farmacocinética
13.
Eur J Cancer ; 62: 46-53, 2016 07.
Artículo en Inglés | MEDLINE | ID: mdl-27208903

RESUMEN

AIM: American phase I studies have reported that the recommended dose of TAS-102 (trifluridine/tipiracil) was 25 mg/m(2) twice a day (b.i.d.), although this schedule did not provide clinically relevant improvements in a phase II study of advanced gastric cancer (AGC). However, a pivotal phase III study revealed that TAS-102 at 35 mg/m(2) b.i.d. provided a clinically relevant improvement in overall survival (OS) among patients with metastatic colorectal cancer. Therefore, we re-evaluated the efficacy, safety, and pharmacokinetic parameters of TAS-102 at 35 mg/m(2) b.i.d among Japanese patients with AGC. METHODS: All patients had undergone one or two previous chemotherapy regimens that contained fluoropyrimidine, platinum agents, and taxanes or irinotecan. The primary end-point target was a disease control rate (DCR) of ≥50% after 8 weeks of the 35 mg/m(2) b.i.d. schedule. RESULTS: Twenty-nine patients were assessable after completing the 35 mg/m(2) b.i.d. schedule. The investigator-determined DCR was 65.5% (95% confidence interval [CI], 45.7-82.1%) and the independent central review's DCR was 51.9% (95% CI, 31.9-71.3%); both results exceeded the primary end-point target. The median progression-free survival and OS were 2.9 months (95% CI, 1.1-5.3 months) and 8.7 months (95% CI, 5.7-14.9 months), respectively. The grade III/IV adverse events included neutropenia (69.0%), leucopaenia (41.4%), anaemia (20.7%), and anorexia (10.3%). No AGC-specific toxicities were detected. CONCLUSIONS: The 35 mg/m(2) b.i.d. dose of TAS-102 provided positive efficacy and an acceptable toxicity profile in patients with AGC. A randomised, double-blind, placebo-controlled, phase III study is ongoing to validate these findings. CLINICAL TRIAL REGISTRATION NUMBER: UMIN000007421.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Gástricas/tratamiento farmacológico , Trifluridina/uso terapéutico , Uracilo/análogos & derivados , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias Colorrectales/tratamiento farmacológico , Supervivencia sin Enfermedad , Método Doble Ciego , Esquema de Medicación , Combinación de Medicamentos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pirrolidinas , Neoplasias Gástricas/patología , Timina , Trifluridina/administración & dosificación , Trifluridina/efectos adversos , Trifluridina/farmacocinética , Uracilo/administración & dosificación , Uracilo/efectos adversos , Uracilo/farmacocinética , Uracilo/uso terapéutico
14.
Cancer Sci ; 107(5): 659-65, 2016 May.
Artículo en Inglés | MEDLINE | ID: mdl-26918279

RESUMEN

TAS-102, a novel oral antitumor agent, consists of trifluridine and tipiracil hydrochloride (molar ratio, 1:0.5). We investigated the effects of food on trifluridine and tipiracil hydrochloride. The efficacy and safety of TAS-102 were evaluated in patients with advanced solid tumors. We analyzed drug pharmacokinetics using a randomized, single-dose, two-treatment (fed versus fasting), two-period, two-sequence cross-over design, followed by repeated administration. Patients were given single doses of TAS-102 (35 mg/m(2) ) in the pharmacokinetic phase and received twice-daily doses of TAS-102 in 28-day cycles in the repeated administration phase for evaluating efficacy and safety. Food showed no effect on the area under the curve from 0 to 12 h or 0 h-infinity values of trifluridine following administration of TAS-102 under fasting and fed conditions, whereas those of tipiracil hydrochloride decreased by approximately 40%. Maximum concentrations of both drugs decreased by approximately 40%, indicating that food influenced the absorption and bioavailability of trifluridine and tipiracil hydrochloride, respectively. During the repeated administration, stable disease was observed in nine patients with rectal, small-cell lung, breast, thymic, duodenal, and prostate cancers. Major adverse events were neutropenia, leukopenia, anemia, and nausea. Postprandial administration was optimal for TAS-102 because trifluridine's area under the curve was not changed by food, indicating that its clinical efficacy would not be affected. Additionally, postprandial administration was reasonable because the maximum concentration of trifluridine decreased in neutrophils, which correlated with previous studies. These results suggest that TAS-102 would be an effective treatment for small-cell lung, thymic, and colorectal cancers. This trial is registered with the Japan Pharmaceutical Information Center (no. JapicCTI-111482).


Asunto(s)
Antineoplásicos/efectos adversos , Antineoplásicos/farmacocinética , Interacciones Alimento-Droga , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Trifluridina/farmacología , Trifluridina/farmacocinética , Uracilo/análogos & derivados , Anciano , Anemia/inducido químicamente , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Área Bajo la Curva , Pueblo Asiatico , Disponibilidad Biológica , Estudios Cruzados , Combinación de Medicamentos , Ayuno , Femenino , Humanos , Japón , Leucopenia/inducido químicamente , Masculino , Persona de Mediana Edad , Náusea/inducido químicamente , Neoplasias/patología , Neutropenia/inducido químicamente , Pirrolidinas/efectos adversos , Pirrolidinas/farmacocinética , Pirrolidinas/farmacología , Pirrolidinas/uso terapéutico , Timina/efectos adversos , Timina/farmacocinética , Timina/farmacología , Timina/uso terapéutico , Trifluridina/efectos adversos , Trifluridina/uso terapéutico , Uracilo/efectos adversos , Uracilo/farmacocinética , Uracilo/farmacología , Uracilo/uso terapéutico
15.
Cancer Chemother Pharmacol ; 77(3): 515-26, 2016 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-26787503

RESUMEN

BACKGROUND: TAS-102 is an oral fluoropyrimidine prodrug composed of trifluridine (FTD) and tipiracil hydrochloride (TPI) in a 1:0.5 ratio. FTD is a thymidine analog, and it is degraded by thymidine phosphorylase (TP) to the inactive trifluoromethyluracil (FTY) metabolite. TPI inhibits degradation of FTD by TP, increasing systemic exposure to FTD. METHODS: Patients with advanced solid tumors (6 M/2 F; median age 58 years; PS 0-1) were enrolled on this study. Patients in group A (N = 4) received 60 mg TAS-102 with 200 nCi [(14)C]-FTD, while patients in group B (N = 4) received 60 mg TAS-102 with 1000 nCi [(14)C]-TPI orally. Plasma, blood, urine, feces, and expired air (group A only) were collected up to 168 h and were analyzed for (14)C by accelerator mass spectrometry and analytes by LC-MS/MS. RESULTS: FTD: 59.8% of the (14)C dose was recovered: 54.8% in urine mostly as FTY and FTD glucuronide isomers. The extractable radioactivity in the pooled plasma consisted of 52.7% FTD and 33.2% FTY. TPI: 76.8% of the (14)C dose was recovered: 27.0% in urine mostly as TPI and 49.7% in feces. The extractable radioactivity in the pooled plasma consisted of 53.1% TPI and 30.9% 6-HMU, the major metabolite of TPI. CONCLUSION: Absorbed (14)C-FTD was metabolized and mostly excreted in urine. The majority of (14)C-TPI was recovered in feces, and the majority of absorbed TPI was excreted in urine. The current data with the ongoing hepatic and renal dysfunction studies will provide an enhanced understanding of the TAS-102 elimination profile.


Asunto(s)
Antineoplásicos/administración & dosificación , Neoplasias/tratamiento farmacológico , Pirimidinas/farmacocinética , Trifluridina/administración & dosificación , Uracilo/análogos & derivados , Anciano , Antineoplásicos/farmacocinética , Cromatografía Liquida/métodos , Combinación de Medicamentos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neoplasias/patología , Pirrolidinas , Espectrometría de Masas en Tándem/métodos , Timidina Fosforilasa/metabolismo , Timina , Trifluridina/farmacocinética , Uracilo/administración & dosificación , Uracilo/farmacocinética
16.
Invest New Drugs ; 33(5): 1068-77, 2015 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-26163340

RESUMEN

BACKGROUND: TAS-102 is a nucleoside antitumor agent consisting of trifluridine (FTD) and tipiracil hydrochloride (TPI). We investigated the recommended dose (RD) of TAS-102 plus irinotecan for metastatic colorectal cancer refractory to 5-fluorouracil (5-FU) and oxaliplatin. METHODS: This study was used a escalated dose of TAS-102 (40-70 mg/m(2)/day, for 5 days a week with 2 days rest for 2 weeks, followed by a 14-day rest) with a fixed dose of irinotecan (150 mg/m(2) on Days 1 and 15 of a 28-day schedule). The primary endpoints were determination of RD and assessment of safety. RESULTS: Ten patients were enrolled; 7 at the Level 1 (50 mg/m(2)/day) and 3 at the Level 2 (60 mg/m(2)/day). One patient at Level 1 was excluded from the analysis of dose-limiting toxicities (DLT) and efficacy. Five DLTs occurred in 3 patients; 1 patient at Level 1 (Grade 3 febrile neutropenia and Grade 4 neutropenia), and 2 patients at Level 2 (Grade 3 febrile neutropenia in two patients and Grade 4 neutropenia in one). Grade 3 or higher treatment-related adverse events were neutropenia (100 %), leukopenia (70 %), febrile neutropenia (30 %) and lymphopenia, anaemia (20 % each). 2 patients (22 %) achieved partial response with the duration of response were 112 and 799 days. CONCLUSION: The RD was determined to be 50 mg/m(2)/day of TAS-102 combined with 150 mg/m(2) of irinotecan although further investigation to explore optimal regimen is warranted.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Área Bajo la Curva , Camptotecina/análogos & derivados , Camptotecina/uso terapéutico , Neoplasias Colorrectales/patología , Relación Dosis-Respuesta a Droga , Combinación de Medicamentos , Femenino , Glucuronosiltransferasa/genética , Humanos , Irinotecán , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Metástasis de la Neoplasia , Polimorfismo Genético , Proteínas Proto-Oncogénicas p21(ras)/genética , Pirrolidinas , Timina , Trifluridina/farmacocinética , Trifluridina/uso terapéutico , Uracilo/análogos & derivados , Uracilo/farmacocinética , Uracilo/uso terapéutico
17.
Cancer Chemother Pharmacol ; 76(2): 325-33, 2015 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-26084259

RESUMEN

PURPOSE: Trifluridine (TFT) is an antitumor component of a novel nucleoside antitumor agent, TAS-102, which consists of TFT and tipiracil hydrochloride (thymidine phosphorylase inhibitor). Incorporation of TFT into DNA is a probable mechanism of antitumor activity and hematological toxicity. The objective of this study was to examine the TFT incorporation into tumor- and white blood cell-DNA, and to elucidate the mechanism of TFT-related effect and toxicity. TFT effect on the colony formation of mouse bone marrow cells was also investigated. METHODS: Pharmacokinetics of TFT was determined in nude mice after single oral administration of TAS-102, while the antitumor activity and body weight change were evaluated in the tumor-bearing nude mice after multiple oral administrations for 2 weeks. TFT concentrations in the blood- and tumor-DNA were determined by LC/MS/MS. The colony formation was evaluated by CFU-GM assay. RESULTS: TFT systemic exposure in plasma increased dose-dependently. The tumor growth rate and body weight gain decreased dose-dependently, but TFT concentrations in the DNA of tumor tissues and white blood cells increased dose-dependently. TFT inhibited colony formation of bone marrow cells in a concentration-dependent manner. CONCLUSIONS: A significant relationship between systemic exposure of TFT and pharmacological effects including the antitumor activity and body weight change was well explained by the TFT incorporation into DNA. TFT inhibited proliferations of mouse bone marrow cells and human colorectal carcinoma cells implanted to nude mice dose-dependently. The highest tolerable TFT exposure provides the highest antitumor activity, and the hematological toxicity may serve as a potential surrogate indicator of TAS-102 efficacy.


Asunto(s)
Antineoplásicos/farmacocinética , Neoplasias del Colon/tratamiento farmacológico , ADN de Neoplasias/metabolismo , Leucocitos/metabolismo , Trifluridina/farmacocinética , Uracilo/análogos & derivados , Animales , Antineoplásicos/efectos adversos , Antineoplásicos/farmacología , Células de la Médula Ósea/efectos de los fármacos , Células de la Médula Ósea/patología , Línea Celular Tumoral , Proliferación Celular , Neoplasias del Colon/sangre , Neoplasias del Colon/patología , Combinación de Medicamentos , Humanos , Ratones Desnudos , Pirrolidinas , Timina , Trifluridina/efectos adversos , Trifluridina/farmacología , Ensayo de Tumor de Célula Madre , Uracilo/efectos adversos , Uracilo/farmacocinética , Uracilo/farmacología
18.
Int J Oncol ; 46(6): 2327-34, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-25901475

RESUMEN

Trifluridine (FTD) and 2'-deoxy-5-fluorouridine (FdUrd), a derivative of 5-fluorouracil (5-FU), are antitumor agents that inhibit thymidylate synthase activity and their nucleotides are incorporated into DNA. However, it is evident that several differences occur in the underlying antitumor mechanisms associated with these nucleoside analogues. Recently, TAS-102 (composed of FTD and tipiracil hydrochloride, TPI) was shown to prolong the survival of patients with colorectal cancer who received a median of 2 prior therapies, including 5-FU. TAS-102 was recently approved for clinical use in Japan. These data suggest that the antitumor activities of TAS-102 and 5-FU proceed via different mechanisms. Thus, we analyzed their properties in terms of thymidine salvage pathway utilization, involving membrane transporters, a nucleoside kinase, a nucleotide-dephosphorylating enzyme, and DNA polymerase α. FTD incorporated into DNA with higher efficiency than FdUrd did. Both FTD and FdUrd were transported into cells by ENT1 and ENT2 and were phosphorylated by thymidine kinase 1, which showed a higher catalytic activity for FTD than for FdUrd. deoxyUTPase (DUT) did not recognize dTTP and FTD-triphosphate (F3dTTP), whereas deoxyuridine-triphosphate (dUTP) and FdUrd-triphosphate (FdUTP) were efficiently degraded by DUT. DNA polymerase α incorporated both F3dTTP and FdUTP into DNA at sites aligned with adenine on the opposite strand. FTD-treated cells showed differing nuclear morphologies compared to FdUrd-treated cells. These findings indicate that FTD and FdUrd are incorporated into DNA with different efficiencies due to differences in the substrate specificities of TK1 and DUT, causing abundant FTD incorporation into DNA.


Asunto(s)
Antimetabolitos Antineoplásicos/farmacología , Neoplasias Colorrectales/genética , ADN de Neoplasias/química , Fluorouracilo/farmacología , Timidina Quinasa/metabolismo , Trifluridina/farmacología , Uracilo/análogos & derivados , Antimetabolitos Antineoplásicos/farmacocinética , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Combinación de Medicamentos , Tranportador Equilibrativo 1 de Nucleósido/metabolismo , Transportador Equilibrativo 2 de Nucleósido/metabolismo , Fluorouracilo/farmacocinética , Células HCT116 , Humanos , Masculino , Pirofosfatasas/metabolismo , Pirrolidinas , Especificidad por Sustrato , Timina , Trifluridina/farmacocinética , Uracilo/farmacocinética , Uracilo/farmacología
19.
Bioconjug Chem ; 24(5): 780-95, 2013 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-23521072

RESUMEN

Herein, we report a novel strategy to engineer an acid-sensitive anticancer theranostic agent using a vector-drug ensemble. The ensemble was synthesized by directly conjugating the linoleic acid (LA)-modified branched polyethyleneimine with a chemotherapeutic drug trifluorothymidine. Linoleic acid residues were grafted onto 25 kDa polyethyleneimine (PEI) by treating PEI with linoleic acid chloroanhydride. 5-Trifluoromethyl-2'-deoxyuridine (trifluorothymidine, TFT) was introduced into LA-PEI conjugate by phosphorylating the conjugate with amidophosphate of trifluorothymidine 5'-monophosphate (pTFT), which had been activated by its conversion into the N,N-dimethylaminopyridine derivative. The extent of mononucleotide analog incorporation in the polymer was regulated by the ratio of pTFT to the polymer during the synthesis. Samples containing 20-70 TFT residues per PEI molecule were obtained. The cytotoxicity of PEI-LA-pTFT conjugates decreased with increasing nucleotide content, as examined using the MTT method. Due to the presence of fluorine atoms, TFT-based conjugates could be detected directly in the animals by (19)F magnetic resonance imaging. In addition, the presence of the amidophosphate group in PEI-LA-pTFT conjugates allowed their detection by in vivo(31)P NMR spectroscopy. Indeed, the (31)P NMR signal of a phosphoramide (δ ~ 12 ppm) was observed in the mouse muscle tissue treated with PEI-LA-pTFT conjugate along with the signals from endogenous phosphorus-containing compounds. At the same time, the use of PEI-LA-pTFT conjugate for chemotherapeutic drug delivery is limited due to the low release of pTFT from the carrier. To enhance the release of the drug from the conjugate in the endosomes, PEI-LA polymer was coupled with urocanic acid (UA), which bears imidazole ring and thus can form an acid-labile P-N bond with pTFT. The PEI-LA-UA-pTFT conjugate containing 30 residues of UA and 40 residues of pTFT was tested against the murine Krebs-II ascites carcinoma, grown as an ascetic tumor. The intraperitoneal injection of the conjugates resulted in prolongation of the animals' life and to the complete disappearance of the tumor after three injections.


Asunto(s)
Antineoplásicos/química , Antineoplásicos/uso terapéutico , Ácido Linoleico/química , Polietileneimina/análogos & derivados , Trifluridina/química , Trifluridina/uso terapéutico , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/farmacocinética , Carcinoma Krebs 2/tratamiento farmacológico , Línea Celular Tumoral , Portadores de Fármacos/química , Humanos , Ligandos , Ratones , Ratones Endogámicos C57BL , Trifluridina/administración & dosificación , Trifluridina/farmacocinética
20.
Br J Cancer ; 107(3): 429-34, 2012 Jul 24.
Artículo en Inglés | MEDLINE | ID: mdl-22735906

RESUMEN

BACKGROUND: TAS-102 consists of α, α, α-trifluorothymidine (TFT) and an inhibitor of thymidine phosphorylase (TPI). We conducted a dose-escalation phase I study in Japanese patients with advanced solid tumours. METHODS: TAS-102 was administered twice daily on days 1-5 and days 8-12 in a 28-day cycle to patients with solid tumours refractory to standard chemotherapy, to determine its maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), and pharmacokinetics (PKs). MTD was evaluated in cycle 1. RESULTS: Safety and PKs were evaluated in 21 patients treated with TAS-102 at 30, 40, 50, 60, or 70 mg m(-2) per day. DLTs, such as grade 4 leucopenia, grade 4 neutropenia, and grade 4 thrombocytopenia, were observed in two patients at doses of 30 and 70 mg m(-2). α, α, α-trifluorothymidine and TPI exposures increased dose dependently, and the percentage of decrease in neutrophil count and TFT exposure were significantly correlated. The disease control rate was 50.0% with a median progression-free survival of 2.4 months in 18 colorectal cancer patients. The dose of TAS-102 was not increased above 70 mg m(-2) per day because of the increased tendency for grade 3 and 4 neutropenia, and 70 mg m(-2) per day was the recommended dose for phase II studies. CONCLUSIONS: TAS-102 at 70 mg m(-2) per day was tolerated in Japanese patients with advanced solid tumours. Phase II studies are ongoing in patients with colorectal cancer.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Neoplasias/tratamiento farmacológico , Timidina Fosforilasa/antagonistas & inhibidores , Trifluridina/administración & dosificación , Uracilo/análogos & derivados , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Pueblo Asiatico , Supervivencia sin Enfermedad , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Combinación de Medicamentos , Femenino , Humanos , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Neoplasias/metabolismo , Pirrolidinas , Timina , Trifluridina/efectos adversos , Trifluridina/farmacocinética , Uracilo/administración & dosificación , Uracilo/efectos adversos , Uracilo/farmacocinética
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