RESUMEN
XELOX therapy, which comprises capecitabine and oxaliplatin, is the standard first-line chemotherapeutic regimen for colorectal cancer. However, its myelosuppressive effects pose challenges for its clinical management. Mathematical modeling combining pharmacokinetics (PK) and toxicodynamics (TD) is a promising approach for optimizing dosing strategies and reducing toxicity. This study aimed to develop a translational PK-TD model using rat data to inform dosing strategies and TD implications in humans. The rats were administered capecitabine, oxaliplatin, or XELOX combination regimen, and PK and TD data were collected. PK parameters were analyzed using sequential compartment analysis, whereas TD responses were assessed using Friberg's semiphysiological model. A toxicity intensity-based nomogram recommends optimal dosing strategies. Translational modeling techniques using the hybrid PK-TD model were employed to predict clinical responses. The PK-TD model successfully predicted the time-course profiles of hematological responses in rats following monotherapy and XELOX combination treatment. Interactive effects on lymphocytopenia were identified with the coadministration of capecitabine and oxaliplatin. A model-based recommended combination of the dose reduction rate for escaping severe lymphocytopenia was proposed as 40% and 60% doses of capecitabine and oxaliplatin, respectively. The current translational model techniques successfully simulated the time-course profiles of blood cell counts with confidence intervals in patients using rat data. Our study provides valuable insights into dose optimization strategies for each individual drug within the XELOX regimen and underscores the potential of translational modeling to improve patient outcomes. In addition to dose determination, these data will lay the groundwork for advancing drug development processes in oncology. SIGNIFICANCE STATEMENT: This study introduced a novel translational modeling approach rooted in a rat PK-TD model to optimize dosing strategies for the XELOX regimen for colorectal cancer treatment. Our findings highlight the interactive effects on lymphocytopenia and suggest a toxicity intensity-based nomogram for dose reduction, thus advancing precision medicine. This translational modeling paradigm enhances our understanding of drug interactions, offering a tool to tailor dosing, minimize hematological toxicity, and improve therapeutic outcomes in patients undergoing XELOX therapy.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica , Capecitabina , Oxaliplatino , Capecitabina/farmacocinética , Capecitabina/administración & dosificación , Animales , Oxaliplatino/farmacocinética , Oxaliplatino/administración & dosificación , Ratas , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Masculino , Relación Dosis-Respuesta a Droga , Ratas Sprague-Dawley , Modelos Biológicos , Investigación Biomédica Traslacional , Fluorouracilo/farmacocinética , Fluorouracilo/análogos & derivados , Fluorouracilo/administración & dosificación , Neoplasias Colorrectales/tratamiento farmacológico , Médula Ósea/efectos de los fármacos , OxaloacetatosRESUMEN
This phase 1b study aimed to evaluate the dose-limiting toxicity (DLT), maximum tolerated dose (MTD), pharmacokinetics, and preliminary efficacy of HR070803, a novel nanoliposomal formulation of irinotecan, in combination with 5-fluorouracil and leucovorin in patients with pretreated advanced solid tumors. This study consisted of dose-escalation and expansion stages. Dose escalation was performed with a traditional 3 + 3 design; patients received intravenous infusion of HR070803 from 60 to 80 mg/m2, followed by leucovorin (200 mg/m2) and 5-fluorouracil (2000 mg/m2) every 2 weeks. In the expansion stage, patients received treatments at selected tolerable dose. Fifteen patients received treatments at 60 mg/m2 (n = 12) and 80 mg/m2 (n = 3). DLTs occurred in 2 patients at 80 mg/m2 (grade 2 neutropenia that resulted in a dose delay of ≥ 7 days, n = 1; grade 3 febrile neutropenia, n = 1). The MTD was determined to be 60 mg/m2. The most frequent HR070803related adverse events included anorexia, leukopenia, neutropenia, nausea, fatigue, and diarrhea. SN-38, the active metabolite of irinotecan, exhibited lower maximum plasma concentrations and a prolonged terminal half-life when irinotecan was administered via nanoliposome compared to conventional injection. Overall, 4 patients achieved a partial response (confirmed, n = 2), and 9 had stable disease. The MTD of HR070803 was 60 mg/m2 when infused with 5-fluorouracil and leucovorin. Nanoliposomal encapsulation modified the pharmacokinetics of irinotecan and SN-38. HR070803 with 5-fluorouracil and leucovorin demonstrated a manageable safety profile and promising antitumor efficacy in advanced solid tumors. TRIAL REGISTRATION: Clinicaltrials.gov, NCT05086848. Retrospectively registered on Oct. 12, 2021.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica , Fluorouracilo , Irinotecán , Leucovorina , Liposomas , Dosis Máxima Tolerada , Neoplasias , Humanos , Leucovorina/administración & dosificación , Leucovorina/farmacocinética , Leucovorina/efectos adversos , Leucovorina/uso terapéutico , Fluorouracilo/administración & dosificación , Fluorouracilo/farmacocinética , Fluorouracilo/efectos adversos , Femenino , Masculino , Persona de Mediana Edad , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Anciano , Irinotecán/farmacocinética , Irinotecán/administración & dosificación , Irinotecán/efectos adversos , Neoplasias/tratamiento farmacológico , Adulto , Relación Dosis-Respuesta a DrogaRESUMEN
BACKGROUND: Peritoneal metastases (PM) commonly occur in colorectal cancer patients. Systemic chemotherapy yields poor outcomes for these patients. It is hypothesised that traditional systemic chemotherapy is not very effective for this patient population. This study investigates to what extent systemic anti-cancer therapy crosses the peritoneal barrier. METHODS: In a Phase I study, eighteen patients received systemic oxaliplatin, 5-FU, and bevacizumab. Plasma and peritoneal fluid samples were collected to measure drug concentrations. A non-compartmental analysis determined the Area Under the Curve (AUC) for oxaliplatin and 5-FU in both matrices. Intraperitoneal (IP) and intravenous (IV) exposure ratios were calculated, along with the bevacizumab concentration IP/IV ratio. The relationship between tumour load and IP/IV ratios and the correlation between the IP/IV ratios of different treatments were assessed statistically. RESULTS: A total of 438 5-FU samples and 578 oxaliplatin samples were analysed in plasma and peritoneal fluid. Bevacizumab was quantified with 17 measurements in plasma and 15 measurements IP. Median IP/IV ratios were 0.143, 0.352 and 0.085 for 5-FU, oxaliplatin and bevacizumab, respectively. Oxaliplatin exhibited a longer IP half-life than 5-FU. A correlation was found between oxaliplatin and bevacizumab IP/IV ratios (R=0.69, p=0.01). No statistical correlations were found between the other investigated drugs. CONCLUSIONS: Our findings indicate that only a small percentage of systemically administered anti-cancer treatment reaches the IP cavity, questioning their efficacy against PM. This strengthens the hypothesis for repeated intraperitoneal chemotherapy to reach adequate anti-cancer drug levels.
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Protocolos de Quimioterapia Combinada Antineoplásica , Bevacizumab , Neoplasias Colorrectales , Fluorouracilo , Oxaliplatino , Neoplasias Peritoneales , Humanos , Bevacizumab/farmacocinética , Bevacizumab/administración & dosificación , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Neoplasias Peritoneales/tratamiento farmacológico , Neoplasias Peritoneales/secundario , Fluorouracilo/farmacocinética , Fluorouracilo/administración & dosificación , Oxaliplatino/farmacocinética , Oxaliplatino/administración & dosificación , Masculino , Persona de Mediana Edad , Femenino , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Adulto , Líquido Ascítico/metabolismo , Área Bajo la Curva , Inyecciones IntraperitonealesRESUMEN
Peritoneal metastases (PM) are common in patients with colorectal cancer. Patients with PM have a poor prognosis, and for those who are not eligible for cytoreductive surgery (CRS) with or without hyperthermic intraperitoneal chemotherapy (HIPEC), palliative chemotherapy is currently the only option. Recently, we conducted a phase I trial (INTERACT) in which irinotecan was administered intraperitoneally (IP) to 18 patients ineligible for CRS-HIPEC. The primary objective was to evaluate covariates influencing the PK profile of irinotecan and SN-38 after IP administration. Secondly, a population PK model was developed to support the further development of IP irinotecan by improving dosing in patients with PM. Patients were treated with IP irinotecan every 2 weeks in combination with systemic FOLFOX-bevacizumab. Irinotecan and SN-38 were measured in plasma (588 samples) and SN-38 was measured in peritoneal fluid (267 samples). Concentration-Time data were log-transformed and analyzed using NONMEM version 7.5 using FOCE+I estimation. An additive error model described the residual error, with inter-individual variability in PK parameters modeled exponentially. The final structural model consisted of five compartments. Weight was identified as a covariate influencing the SN-38 plasma volume of distribution and GGT was found to influence the SN-38 plasma clearance. This population PK model adequately described the irinotecan and SN-38 in plasma after IP administration, with weight and GGT as predictive factors. Irinotecan is converted intraperitoneal to SN-38 by carboxylesterases and the plasma bioavailability of irinotecan is low. This model will be used for the further clinical development of IP irinotecan by providing dosing strategies.
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Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias Colorrectales , Irinotecán , Neoplasias Peritoneales , Humanos , Irinotecán/farmacocinética , Irinotecán/administración & dosificación , Neoplasias Peritoneales/secundario , Neoplasias Peritoneales/tratamiento farmacológico , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Masculino , Persona de Mediana Edad , Femenino , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Adulto , Camptotecina/análogos & derivados , Camptotecina/farmacocinética , Camptotecina/administración & dosificación , Camptotecina/uso terapéutico , Modelos Biológicos , Bevacizumab/farmacocinética , Bevacizumab/administración & dosificación , Bevacizumab/uso terapéutico , Leucovorina/farmacocinética , Leucovorina/administración & dosificación , Leucovorina/uso terapéutico , Fluorouracilo/farmacocinética , Fluorouracilo/administración & dosificación , Inyecciones Intraperitoneales , Compuestos OrganoplatinosRESUMEN
BACKGROUND: Dosing of chemotherapies is often calculated according to the weight and/or height of the patient or equations derived from these, such as body surface area (BSA). Such calculations fail to capture intra- and interindividual pharmacokinetic variation, which can lead to order of magnitude variations in systemic chemotherapy levels and thus under- or overdosing of patients. METHODS: We designed and developed a closed-loop drug delivery system that can dynamically adjust its infusion rate to the patient to reach and maintain the drug's target concentration, regardless of a patient's pharmacokinetics (PK). FINDINGS: We demonstrate that closed-loop automated drug infusion regulator (CLAUDIA) can control the concentration of 5-fluorouracil (5-FU) in rabbits according to a range of concentration-time profiles (which could be useful in chronomodulated chemotherapy) and over a range of PK conditions that mimic the PK variability observed clinically. In one set of experiments, BSA-based dosing resulted in a concentration 7 times above the target range, while CLAUDIA keeps the concentration of 5-FU in or near the targeted range. Further, we demonstrate that CLAUDIA is cost effective compared to BSA-based dosing. CONCLUSIONS: We anticipate that CLAUDIA could be rapidly translated to the clinic to enable physicians to control the plasma concentration of chemotherapy in their patients. FUNDING: This work was supported by MIT's Karl van Tassel (1925) Career Development Professorship and Department of Mechanical Engineering and the Bridge Project, a partnership between the Koch Institute for Integrative Cancer Research at MIT and the Dana-Farber/Harvard Cancer Center.
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Sistemas de Liberación de Medicamentos , Fluorouracilo , Medicina de Precisión , Fluorouracilo/farmacocinética , Fluorouracilo/administración & dosificación , Conejos , Animales , Sistemas de Liberación de Medicamentos/métodos , Medicina de Precisión/métodos , Humanos , Infusiones Intravenosas , Antimetabolitos Antineoplásicos/farmacocinética , Antimetabolitos Antineoplásicos/administración & dosificaciónRESUMEN
The discovery of circadian clock genes greatly amplified the study of diurnal variations impacting cancer therapy, transforming it into a rapidly growing field of research. Especially, use of chronomodulated treatment with 5-fluorouracil (5-FU) has gained significance. Studies indicate high interindividual variability (IIV) in diurnal variations in dihydropyrimidine dehydrogenase (DPD) activity - a key enzyme for 5-FU metabolism. However, the influence of individual DPD chronotypes on chronomodulated therapy remains unclear and warrants further investigation. To optimize precision dosing of chronomodulated 5-FU, this study aims to: (i) build physiologically-based pharmacokinetic (PBPK) models for 5-FU, uracil, and their metabolites, (ii) assess the impact of diurnal variation on DPD activity, (iii) estimate individual DPD chronotypes, and (iv) personalize chronomodulated 5-FU infusion rates based on a patient's DPD chronotype. Whole-body PBPK models were developed with PK-Sim(R) and MoBi(R). Sinusoidal functions were used to incorporate variations in enzyme activity and chronomodulated infusion rates as well as to estimate individual DPD chronotypes from DPYD mRNA expression or DPD enzymatic activity. Four whole-body PBPK models for 5-FU, uracil, and their metabolites were established utilizing data from 41 5-FU and 10 publicly available uracil studies. IIV in DPD chronotypes was assessed and personalized chronomodulated administrations were developed to achieve (i) comparable 5-FU peak plasma concentrations, (ii) comparable 5-FU exposure, and (iii) constant 5-FU plasma levels via "noise cancellation" chronomodulated infusion. The developed PBPK models capture the extent of diurnal variations in DPD activity and can help investigate individualized chronomodulated 5-FU therapy through testing alternative personalized dosing strategies.
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Antimetabolitos Antineoplásicos , Ritmo Circadiano , Dihidrouracilo Deshidrogenasa (NADP) , Fluorouracilo , Modelos Biológicos , Neoplasias , Medicina de Precisión , Fluorouracilo/farmacocinética , Fluorouracilo/administración & dosificación , Humanos , Dihidrouracilo Deshidrogenasa (NADP)/metabolismo , Dihidrouracilo Deshidrogenasa (NADP)/genética , Antimetabolitos Antineoplásicos/farmacocinética , Antimetabolitos Antineoplásicos/administración & dosificación , Medicina de Precisión/métodos , Neoplasias/tratamiento farmacológico , Ritmo Circadiano/fisiología , Cronoterapia de Medicamentos , Masculino , Femenino , Simulación por Computador , Persona de Mediana Edad , Uracilo/farmacocinética , Uracilo/administración & dosificación , Uracilo/análogos & derivadosRESUMEN
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.
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Lesión Renal Aguda , Neoplasias Colorrectales , Humanos , Ratas , Animales , Oxaliplatino , Tegafur/toxicidad , Tegafur/farmacocinética , Fluorouracilo/uso terapéutico , Fluorouracilo/farmacocinética , Riñón/patología , Lesión Renal Aguda/inducido químicamente , Lesión Renal Aguda/tratamiento farmacológico , Biomarcadores , Neoplasias Colorrectales/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéuticoRESUMEN
BACKGROUND: Capecitabine is an oral chemotherapy prodrug of 5-fluorouracil (5-FU) with unpredictable toxicity, especially in older adults. The aim of this study was to evaluate the pharmacokinetics (PK) of capecitabine and its metabolites in younger adults (< 70 years) and older adults (≥ 70 years) receiving capecitabine for solid cancer. METHODS: Eligible participants receiving capecitabine had 2 venous samples collected on day 14 of cycle 1 and cycle 2 of their treatment. Capecitabine and metabolite concentrations were determined using liquid chromatography with tandem mass spectrometry. A Bayesian estimation approach was used to generate individual estimates of PK parameters for 5-FU. A linear mixed-effect analysis of variance (ANOVA) model was used to compare dose-normalised log-transformed PK parameters between age groups. Correlations were determined by linear regression and logistic regression analyses. RESULTS: Of the total 26 participants, 58% were male with a median age of 67 years (range, 37-85) with 54% aged < 70 years and 46% aged ≥ 70 years. Participants aged ≥ 70 years, compared to those aged < 70 years, had a greater 5-FU exposure based on area under the concentration-time curve (AUC) of 17% (90% CI 103-134%; 0.893 vs. 0.762 mg h/L) and 14% increase in maximal concentration, Cmax (90% CI 82.1-159%; 0.343 vs. 0.300 mg/L). The 5-FU Cmax was positively associated with time up and go (TUG) (Pearson's correlation 0.77, p = 0.01), but not other geriatric assessment domains or severe toxicity. CONCLUSION: 5-FU exposure was significantly increased in older adults compared to younger adults receiving equivalent doses of capecitabine, and is a possible cause for increased toxicity in older adults.
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Desoxicitidina , Neoplasias , Masculino , Humanos , Anciano , Adulto , Persona de Mediana Edad , Anciano de 80 o más Años , Femenino , Capecitabina/efectos adversos , Proyectos Piloto , Teorema de Bayes , Área Bajo la Curva , Fluorouracilo/farmacocinética , Neoplasias/tratamiento farmacológicoRESUMEN
Aim: To develop a new sensitive RP-HPLC method for simultaneous estimation of 5-fluorouracil (5-FU) and sonidegib (SDG). Materials & methods: Analytical and bioanalytical methods for simultaneous quantification of 5-FU and SDG in bulk, nanoformulations and in rat plasma were developed and validated using a gradient elution technique. Results: Separation of the analytes was effected on a Luna® C18 LC column using a mobile mixture comprising acetonitrile and acidified water. 5-FU and SDG were extracted from plasma matrix using liquid-liquid extraction. The applicability of the method was verified through single-dose oral pharmacokinetic study in Wistar rats. Conclusion: The developed methods allow a specific, sensitive and steady analytical procedure for the simultaneous estimation of 5-FU and SDG in nanoformulations and biological matrix.
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Compuestos de Bifenilo/farmacocinética , Fluorouracilo/farmacocinética , Neoplasias/tratamiento farmacológico , Piridinas/farmacocinética , Animales , Cromatografía Líquida de Alta Presión/métodos , Masculino , Ratas , Ratas WistarRESUMEN
Pharmacokinetic (PK) studies improve the design of dosing regimens in preclinical and clinical settings. In complex diseases like cancer, single-agent approaches are often insufficient for an effective treatment, and drug combination therapies can be implemented. In this work, in silico PK models were developed based on in vitro assays results, with the goal of predicting the in vivo performance of drug combinations in the context of cancer therapy. Combinations of reference drugs for cancer treatment, gemcitabine and 5-fluorouracil (5-FU), and repurposed drugs itraconazole, verapamil or tacrine, were evaluated in vitro. Then, two-compartment PK models were developed based on the previous in vitro studies and on the PK profile reported in the literature for human patients. Considering the quantification parameter area under the dose-response-time curve (AUCeffect) for the combinations effect, itraconazole was the most effective in combination with either reference anticancer drugs. In addition, cell growth inhibition was itraconazole-dose dependent and an increase in effect was predicted if itraconazole administration was continued (24-h dosing interval). This work demonstrates that in silico methods and AUCeffect are powerful tools to study relationships between tissue drug concentration and the percentage of cell growth inhibition over time.
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Antineoplásicos/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Desoxicitidina/análogos & derivados , Fluorouracilo/farmacología , Antineoplásicos/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Simulación por Computador , Desoxicitidina/farmacocinética , Desoxicitidina/farmacología , Combinación de Medicamentos , Fluorouracilo/farmacocinética , Humanos , Modelos Biológicos , Neoplasias/tratamiento farmacológico , GemcitabinaRESUMEN
PURPOSE: Fluoropyrimidines are one of the most used drug class to treat cancer patients, although they show high levels of associated toxicity. This study analyzed 33 polymorphisms in 17 pharmacogenes involved with the pharmacogenomics of fluoropyrimidines, in gastrointestinal cancer patients undergoing fluoropyrimidine-based treatment in the Brazilian Amazon. METHODS: The study population was composed of 216 patients, 92 of whom have an anatomopathological diagnosis of gastric cancer and 124 of colorectal cancer. The single nucleotide polymorphisms (SNP) were genotyped by allelic discrimination using the TaqMan OpenArray Genotyping technology, with a panel of 32 customized assays, run in a QuantStudio ™ 12K Flex Real-Time PCR System (Applied Biosystems, Life Technologies, Carlsbad USA). Ancestry analysis was performed using 61 autosomal ancestry informative markers (AIMs). RESULTS: The study population show mean values of 48.1% European, 31.1% Amerindian, and 20.8% African ancestries. A significant risk association for general and severe toxicity was found in the rs4451422 of FPGS (p = 0.001; OR 3.40; CI 95% 1.65-7.00 and p = 0.006; OR 4.63; CI 95% 1.56-13.72, respectively) and the rs9524885 of ABCC4 (p = 0.023; OR 2.74; CI 95% 1.14-6.65 and p = 0.024; OR 5.36; IC 95% 1.24-23.11, respectively) genes. The rs760370 in the SLC29A1 gene (p = 0.009; OR 6.71; CI 95% 1.16-8.21) and the rs1801133 in the MTHFR toxicity (p = 0.023; OR 3.09; CI 95% 1.16-8.21) gene also demonstrated to be significant, although only for severe toxicity. The results found in this study did not have statistics analysis correction. CONCLUSION: Four polymorphisms of the ABCC4, FPGS, SLC29A1, and MTHFR genes are likely to be potential predictive biomarkers for precision medicine in fluoropyrimidine-based treatments in the population of the Brazilian Amazon, which is constituted by a unique genetic background.
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Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Neoplasias Gastrointestinales/tratamiento farmacológico , Neoplasias Gastrointestinales/genética , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Brasil , Camptotecina/análogos & derivados , Camptotecina/farmacología , Tranportador Equilibrativo 1 de Nucleósido/genética , Femenino , Fluorouracilo/administración & dosificación , Fluorouracilo/farmacocinética , Fluorouracilo/farmacología , Humanos , Leucovorina/farmacología , Masculino , Metilenotetrahidrofolato Reductasa (NADPH2)/genética , Persona de Mediana Edad , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/genética , Compuestos Organoplatinos/farmacología , Péptido Sintasas/genética , Variantes Farmacogenómicas , Polimorfismo de Nucleótido SimpleRESUMEN
To prepare glutaraldehyde-based cross-linked medium molecular weight chitosan nanoparticles encapsulated with 5-Fluorouracil (5-FU), to overcome dosing frequency as well as reducing acute oral toxicity and poor bioavailability of the drug. Medium molecular weight chitosan nanoparticles (MMWCH-NPs) were prepared by reverse micelles method based on glutaraldehyde (GA) cross-linking and optimized by the process as well as formulation variables like a various drug to polymer ratio, cross-linker volumes, varying stirring speeds (rpm), different time of rotation/stirring, respectively and their effects on the mean particles size distribution and entrapment efficiency %EE and %LC of NPs. Characterization of formulations was done by FTIR studies, TEM, PXRD, TGA, Stability, and dissolution drug release studies were performed by dialysis bag technique at both pH (1.2 & 7.4) and acute oral toxicity studies in albino rabbits. The formulated nanoparticles showed a smooth morphology with smaller particle size distribution (230-550 nm), zeta potential (-15 to -18 mV) required to achieve enhanced permeation and retention effect (EPR), entrapment efficiency (%EE 12-59%). These NPs exhibited a controlled drug release profile with 84.36% of the drug over a period of 24 h. Drug release data were fitted to different kinetic models which predominantly followed Fickian diffusion mechanism (R2 = 0.972-0.976, N = 0.326-0.256). The optimized formulation (5-FU6) was observed under DSC/TGA, TEM. PXRD curves, FTIR, which confirmed thermal stability, structural integrity, amorphous state, compatibility between drug and polymer of optimized (5-FU6) as well as reduced acute oral toxicity in albino rabbits. Cross-linked medium molecular weight chitosan nanoparticles are nontoxic, well-tolerated therefore could be the future candidate for therapeutic effects as novel drug delivery carrier for anticancer drug(s).
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Antineoplásicos/administración & dosificación , Quitosano/química , Fluorouracilo/administración & dosificación , Nanopartículas/química , Animales , Antineoplásicos/efectos adversos , Antineoplásicos/farmacocinética , Química Farmacéutica , Preparaciones de Acción Retardada , Portadores de Fármacos , Liberación de Fármacos , Estabilidad de Medicamentos , Fluorouracilo/efectos adversos , Fluorouracilo/farmacocinética , Glutaral/química , Peso Molecular , Enfermedades de la Boca/inducido químicamente , Enfermedades de la Boca/prevención & control , Tamaño de la Partícula , ConejosRESUMEN
BACKGROUND: A low skeletal muscle mass (SMM) has been associated with increased toxicity and shorter survival in cancer patients treated with capecitabine, an oral prodrug of 5-fluorouracil (5-FU). Capecitabine and its metabolites are highly water-soluble and, therefore, more likely to distribute to lean tissues. The pharmacokinetics (PK) in patients with a low SMM could be changed, for example, by reaching higher maximum plasma concentrations. In this study, we aimed to examine whether the association between a low SMM and increased toxicity and shorter survival could be explained by altered PK of capecitabine and its metabolites. METHODS: Previously, a population PK model of capecitabine and metabolites in patients with solid tumors was developed. In our analysis, we included patients from this previous analysis for which evaluable abdominal computed tomography (CT)-scans were available. SMM was measured on CT-scans, by single slice evaluation at the third lumbar vertebra, using the Slice-o-Matic software. The previously developed population PK model was extended with SMM as a covariate, to assess the association between SMM and capecitabine and metabolite PK. RESULTS: PK and SMM data were available from 151 cancer patients with solid tumors. From the included patients, 55% had a low SMM. No relevant relationships were found between SMM and the PK parameters of capecitabine and, the active and toxic metabolite, 5-FU. SMM only correlated with the PK of the, most hydrophilic, but inactive and non-toxic, metabolite α-fluoro-ß-alanine (FBAL). Patients with a low SMM had a smaller apparent volume of distribution and lower apparent clearance of FBAL. CONCLUSIONS: No alterations in PK of capecitabine and the active and toxic metabolite 5-FU were observed in patients with a low SMM. Therefore, the previously identified increased toxicity and shorter survival in patients with a low SMM, could not be explained by changes in pharmacokinetic characteristics of capecitabine and metabolites.
Asunto(s)
Antimetabolitos Antineoplásicos/farmacocinética , Capecitabina/farmacocinética , Músculo Esquelético/metabolismo , Neoplasias/metabolismo , Adulto , Anciano , Antimetabolitos Antineoplásicos/administración & dosificación , Antimetabolitos Antineoplásicos/efectos adversos , Capecitabina/administración & dosificación , Capecitabina/efectos adversos , Femenino , Fluorouracilo/farmacocinética , Humanos , Masculino , Persona de Mediana Edad , Músculo Esquelético/diagnóstico por imagen , Músculo Esquelético/patología , Neoplasias/tratamiento farmacológico , Neoplasias/mortalidad , Profármacos/administración & dosificación , Profármacos/efectos adversos , Profármacos/farmacocinética , Factores Sexuales , Tomografía Computarizada por Rayos X , Resultado del Tratamiento , beta-Alanina/análogos & derivados , beta-Alanina/farmacocinéticaRESUMEN
5-Fluorouracil (5-FU) is a widely used chemotherapeutical that induces acute toxicity in the small and large intestine of patients. Symptoms can be severe and lead to the interruption of cancer treatments. However, there is limited understanding of the molecular mechanisms underlying 5-FU-induced intestinal toxicity. In this study, well-established 3D organoid models of human colon and small intestine (SI) were used to characterize 5-FU transcriptomic and metabolomic responses. Clinically relevant 5-FU concentrations for in vitro testing in organoids were established using physiologically based pharmacokinetic simulation of dosing regimens recommended for cancer patients, resulting in exposures to 10, 100 and 1000 µM. After treatment, different measurements were performed: cell viability and apoptosis; image analysis of cell morphological changes; RNA sequencing; and metabolome analysis of supernatant from organoids cultures. Based on analysis of the differentially expressed genes, the most prominent molecular pathways affected by 5-FU included cell cycle, p53 signalling, mitochondrial ATP synthesis and apoptosis. Short time-series expression miner demonstrated tissue-specific mechanisms affected by 5-FU, namely biosynthesis and transport of small molecules, and mRNA translation for colon; cell signalling mediated by Rho GTPases and fork-head box transcription factors for SI. Metabolomic analysis showed that in addition to the effects on TCA cycle and oxidative stress in both organoids, tissue-specific metabolic alterations were also induced by 5-FU. Multi-omics integration identified transcription factor E2F1, a regulator of cell cycle and apoptosis, as the best key node across all samples. These results provide new insights into 5-FU toxicity mechanisms and underline the relevance of human organoid models in the safety assessment in drug development.
Asunto(s)
Colon/efectos de los fármacos , Fluorouracilo/toxicidad , Intestino Delgado/efectos de los fármacos , Modelos Biológicos , Antimetabolitos Antineoplásicos/administración & dosificación , Antimetabolitos Antineoplásicos/farmacocinética , Antimetabolitos Antineoplásicos/toxicidad , Apoptosis/efectos de los fármacos , Ciclo Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Colon/patología , Relación Dosis-Respuesta a Droga , Femenino , Fluorouracilo/administración & dosificación , Fluorouracilo/farmacocinética , Humanos , Intestino Delgado/patología , Masculino , Metabolómica , Organoides/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , TranscriptomaRESUMEN
PURPOSE: The aim was to investigate the pharmacokinetics of preoperatively administered intraperitoneal (IP) 5-FU in patients with resectable pancreatic ductal adenocarcinoma (PDAC) by analyzing levels of 5-FU and target metabolites in peritoneal fluid, plasma, liver, lymph nodes, pancreatic tumour, and pancreatic tissue. These results were correlated to expression of genes encoding enzymes of the 5-FU pathway and cell membrane transporters of 5-FU and FdUMP. METHODS: Twenty-two patients with PDAC were treated with IP 5-FU before surgery. The postoperative treatment followed a routine clinical protocol. 5-FU and its metabolites were analyzed by LC-MS/MS. The expression of genes encoding enzymes and transporters in the 5-FU pathway was analyzed by qPCR. RESULTS: After IP treatment, 5-FU could be detected in plasma, lymph nodes, liver, pancreatic tumour, and pancreatic tissue. The highest 5-FU concentration was found in the liver, also expressing high levels of the 5-FU transporter OAT2. 5-FU was converted to active FdUMP in all tissues and the highest concentration was measured in lymph nodes, liver and pancreatic tumour (18.5, 6.1 and 6.7 pmol/g, respectively). There was a correlation between the FdUMP and dUr levels in lymph nodes (r = 0.70, p = 0.0076). In tumours, there was an association between OAT2 expression and FdUMP concentration. CONCLUSION: The study shows uptake of IP 5-FU and drug metabolism to active FdUMP in pancreatic tumour, liver, and lymph nodes. Extended studies are warranted to evaluate the IP route for 5-FU administration in PDAC patients.
Asunto(s)
Antimetabolitos Antineoplásicos/administración & dosificación , Carcinoma Ductal Pancreático/terapia , Fluorouracilo/administración & dosificación , Neoplasias Pancreáticas/terapia , Anciano , Antimetabolitos Antineoplásicos/farmacocinética , Carcinoma Ductal Pancreático/patología , Cromatografía Liquida , Terapia Combinada , Femenino , Fluorouracilo/farmacocinética , Humanos , Inyecciones Intraperitoneales , Masculino , Persona de Mediana Edad , Neoplasias Pancreáticas/patología , Cuidados Preoperatorios/métodos , Espectrometría de Masas en Tándem , Distribución TisularRESUMEN
In the present study, combinatorial nanostructured lipid carrier gel of 5-fluorouracil and resveratrol was formulated, optimized and characterized to enhance permeation in between epidermis and dermis layers of the skin to obtain a synergistic effect against skin cancer. After extensive trials, a newly modified emulsiosonication method was developed and additionally, for the first time, stability studies were done in the beginning to optimize formulation technique, which exhibited two major benefits simultaneously; first, it provided best-optimized technique for preparation of combinatorial lipid-nanosystem, and secondly, it also demonstrated a detailed report card of durability of formulations. In vitro release study showed a significantly improved, slow and prolonged release of drugs from the optimized lipid-nanosystem (***p < 0.05), which followed non-Fickian Higuchi kinetics. Besides, mechanism of skin permeation enhancement study, dermatokinetic assessment, and depth analysis of optimized formulation on skin exhibited improved permeation and well distribution of drugs up to the dermis layer of skin. Moreover, combinatorial linogel possessed significantly greater efficacy (**p < 0.01) on the A431 cell line, as compared to the conventional formulation. Thus, findings revealed that modified method of preparation for dual drug-loaded lipid-nanosystem lead to the production of a stable formulation that also improved the retention of both 5-fluorouracil and resveratrol in between the epidermis and dermis region of skin thereby helping in the management and treatment of skin cancer.
Asunto(s)
Antineoplásicos/administración & dosificación , Portadores de Fármacos/química , Fluorouracilo/administración & dosificación , Resveratrol/administración & dosificación , Neoplasias Cutáneas/tratamiento farmacológico , Administración Cutánea , Animales , Antineoplásicos/farmacocinética , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Preparaciones de Acción Retardada/administración & dosificación , Preparaciones de Acción Retardada/farmacocinética , Combinación de Medicamentos , Composición de Medicamentos/métodos , Liberación de Fármacos , Excipientes/química , Fluorouracilo/farmacocinética , Humanos , Lípidos/química , Nanopartículas/química , Tamaño de la Partícula , Ratas , Resveratrol/farmacocinética , Piel/metabolismo , Piel/patología , Absorción Cutánea , Neoplasias Cutáneas/patología , Distribución TisularRESUMEN
As one of the most prevalent and deadly cancers worldwide, esophageal squamous cell carcinoma (ESCC) can be directly exposed to endocrine-disrupting chemical (EDC). As a potential EDC, diethylhexyl phthalate (DEHP) can trigger the development of various cancers, while the potential effect of DEHP on the ESCC progression was not clear. Our present study revealed that DEHP can trigger the proliferation of ESCC cells and decrease the cisplatin (CDDP) and fluorouracil (5-FU) sensitivity. Mechanistical studies indicated that DEHP can decrease the transcription of PTEN, a well-characterized tumor suppressor, in ESCC cells. Over expression of PTEN can reverse DEHP-regulated ESCC cell proliferation and chemosensitivity. Further, DEHP can increase the expression of HES-1, which can bind with the promoter of PTEN to inhibit its transcription. Collectively, DEHP can increase proliferation while decrease chemosensitivity of ESCC cells via regulation of HES-1/PTEN axis. Further, daily expression of DEHP may be a potent risk factor for ESCC development.
Asunto(s)
Antineoplásicos/farmacología , Proliferación Celular/efectos de los fármacos , Cisplatino/farmacología , Dietilhexil Ftalato/efectos adversos , Disruptores Endocrinos/efectos adversos , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/patología , Carcinoma de Células Escamosas de Esófago/genética , Carcinoma de Células Escamosas de Esófago/patología , Fluorouracilo/farmacocinética , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Genes Supresores de Tumor , Fosfohidrolasa PTEN/genética , Fosfohidrolasa PTEN/metabolismo , Transcripción Genética/efectos de los fármacos , Línea Celular Tumoral , Progresión de la Enfermedad , Resistencia a Antineoplásicos/efectos de los fármacos , Expresión Génica/efectos de los fármacos , Humanos , Unión Proteica , Factor de Transcripción HES-1/genética , Factor de Transcripción HES-1/metabolismo , Transcripción Genética/genéticaRESUMEN
Polymer-clay nanocomposite hydrogel films (PCNCHFs) were prepared from caboxymethyl cellulose, polyvinylpyrrolidone, agar and nanosepiolite clay (0, 0.3, 0.5, 0.7, 0.9 and 1.5% reinforcement) by treating thermally in a simple, rapid, and inexpensive route. The PCNCHFs and its 5-fluorouracil (FU)-loaded composites (PCNCHFs@FU) were tested for FU release and characterized by FTIR, XRD, FE-SEM, EDX, DSC, and TGA analyses to investigate their structural, morphological, and thermal properties. The nanosepiolite-loaded polymer composites (PCNCHF1 to PCNCHF5) exhibited higher tensile strength than the pristine polymer hydrogel (PCNCHF0); consequently, the thermal properties (glass- and melting-transition) were improved. The PCNCHFs@FU demonstrated prolonged FU release at pH 7.4 for 32 h. The biocompatibility of PCNCHFs was tested against human skin fibroblast (CCDK) cells. The viability of cells exposed to all PCNCHFs was >95% after 72 h of culture. The live/dead assay show the proliferation of fibroblast cells, confirming the biocompatibility of the hydrogels. The pH-sensitive PCNCHFs@FU release could be suitable for drug release in cancer therapy, and the developed PCNCHFs may also be useful for tissue engineering, food packaging, and other biological applications.
Asunto(s)
Carboximetilcelulosa de Sodio/química , Portadores de Fármacos/química , Fluorouracilo , Hidrogeles/química , Silicatos de Magnesio/química , Nanocompuestos/química , Fluorouracilo/química , Fluorouracilo/farmacocinéticaRESUMEN
Overcoming drug resistance is one of the biggest challenges in cancer chemotherapy. In this study, we examine whether targeting the long noncoding RNA taurine upregulated gene 1 (TUG1) could be an effective therapeutic approach to overcome drug resistance in pancreatic ductal adenocarcinoma (PDAC). TUG1 was expressed at significantly higher levels across 197 PDAC tissues compared with normal pancreatic tissues. Overall survival of patients with PDAC who had undergone 5-FU-based chemotherapy was shorter in high TUG1 group than in low TUG1 group. Mechanistically, TUG1 antagonized miR-376b-3p and upregulated dihydropyrimidine dehydrogenase (DPD). TUG1 depletion induced susceptibility to 5-FU in BxPC-3 and PK-9 pancreatic cell lines. Consistently, the cellular concentration of 5-FU was significantly higher under TUG1-depleted conditions. In PDAC xenograft models, intravenous treatment with a cancer-specific drug delivery system (TUG1-DDS) and 5-FU significantly suppressed PDAC tumor growth compared with 5-FU treatment alone. This novel approach using TUG1-DDS in combination with 5-FU may serve as an effective therapeutic option to attenuate DPD activity and meet appropriate 5-FU dosage requirements in targeted PDAC cells, which can reduce the systemic adverse effects of chemotherapy. SIGNIFICANCE: Targeting TUG1 coupled with a cancer-specific drug delivery system effectively modulates 5-FU catabolism in TUG1-overexpressing PDAC cells, thus contributing to a new combinatorial strategy for cancer treatment. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/81/7/1654/F1.large.jpg.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma Ductal Pancreático/tratamiento farmacológico , Oligonucleótidos Antisentido/administración & dosificación , Neoplasias Pancreáticas/tratamiento farmacológico , ARN Largo no Codificante/antagonistas & inhibidores , Animales , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patología , Línea Celular Tumoral , Estudios de Cohortes , Sistemas de Liberación de Medicamentos/métodos , Sinergismo Farmacológico , Femenino , Fluorouracilo/administración & dosificación , Fluorouracilo/farmacocinética , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Inactivación Metabólica/efectos de los fármacos , Ratones , Ratones Endogámicos NOD , Ratones SCID , Terapia Molecular Dirigida/métodos , Especificidad de Órganos/efectos de los fármacos , Especificidad de Órganos/genética , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patología , Péptidos Cíclicos/administración & dosificación , Péptidos Cíclicos/química , ARN Largo no Codificante/efectos de los fármacos , ARN Largo no Codificante/genética , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Consensus guidelines exist for genotype-guided fluoropyrimidine dosing based on variation in the gene dihydropyrimidine dehydrogenase (DPYD). However, these guidelines have not been widely implemented in North America and most studies of pretreatment DPYD screening have been conducted in Europe. Given regional differences in treatment practices and rates of adverse events (AEs), we investigated the impact of pretreatment DPYD genotyping on AEs in a Canadian context. Patients referred for DPYD genotyping prior to fluoropyrimidine treatment were enrolled from December 2013 through November 2019 and followed until completion of fluoropyrimidine treatment. Patients were genotyped for DPYD c.1905+1G>A, c.2846A>T, c.1679T>G, and c.1236G>A. Genotype-guided dosing recommendations were informed by Clinical Pharmacogenetics Implementation Consortium guidelines. The primary outcome was the proportion of patients who experienced a severe fluoropyrimidine-related AE (grade ≥3, Common Terminology Criteria for Adverse Events version 5.0). Secondary outcomes included early severe AEs, severe AEs by toxicity category, discontinuation of fluoropyrimidine treatment due to AEs, and fluoropyrimidine-related death. Among 1394 patients, mean (SD) age was 64 (12) years, 764 (54.8%) were men, and 47 (3.4%) were DPYD variant carriers treated with dose reduction. Eleven variant carriers (23%) and 418 (31.0%) noncarriers experienced a severe fluoropyrimidine-related AE (p = 0.265). Six carriers (15%) and 284 noncarriers (21.1%) experienced early severe fluoropyrimidine-related AEs (p = 0.167). DPYD variant carriers treated with genotype-guided dosing did not experience an increased risk for severe AEs. Our data support a role for DPYD genotyping in the use of fluoropyrimidines in North America.