RESUMO
Background and Objectives: Gemcitabine has been used to treat various solid cancers, including, since 1997, metastatic pancreatic cancer. Here, we developed an HPLC-UV method to determine serum gemcitabine levels and use it in pharmacokinetic studies. Materials and Methods: The analysis was performed after a single protein precipitation step on a reversed-phase column, isocratically eluted with sodium phosphate buffer and methanol. For the pharmacokinetic study, NOD/SCID mice received a single dose of gemcitabine at 100 mg/kg by either subcutaneous (SC) or intraperitoneal (IP) administration. Blood samples were collected at 5, 15, and 30 min and 1, 2, 4, and 6 h after the administration of gemcitabine for further analysis. Results: The duration of the analysis was ~12.5 min. The calibration curve was linear (r2 = 0.999) over the range of 1-400 µM. The mean recovery of GEM was 96.53% and the limit of detection was 0.166 µΜ. T1/2, Tmax, Cmax, AUC0-t, and clearance were 64.49 min, 5.00 min, 264.88 µmol/L, 9351.95 µmol/L*min, and 0.0103(mg)/(µmol/L)/min, respectively, for the SC administration. The corresponding values for the IP administration were 59.34 min, 5.00 min, 300.73 µmol/L, 8981.35 µmol/L*min and 0.0108(mg)/(µmol/L)/min (not statistically different from the SC administration). Conclusions: A simple, valid, sensitive, and inexpensive method for the measurement of gemcitabine in serum has been developed. This method may be useful for monitoring gemcitabine levels in cancer patients as part of therapeutic drug monitoring.
Assuntos
Desoxicitidina , Gencitabina , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacocinética , Desoxicitidina/sangue , Desoxicitidina/uso terapêutico , Cromatografia Líquida de Alta Pressão/métodos , Animais , Camundongos , Reprodutibilidade dos Testes , Camundongos SCID , Antimetabólitos Antineoplásicos/farmacocinética , Antimetabólitos Antineoplásicos/sangue , Camundongos Endogâmicos NODRESUMO
BACKGROUND AND OBJECTIVES: Methotrexate is widely utilized in the chemotherapy of malignant tumors and autoimmune diseases in the pediatric population, but dosing can be challenging. Several population pharmacokinetic models were developed to characterize factors influencing variability and improve individualization of dosing regimens. However, significant covariates included varied across studies. The primary objective of this review was to summarize and discuss population pharmacokinetic models of methotrexate and covariates that influence pharmacokinetic variability in pediatric patients. METHODS: Systematic searches were conducted in the PubMed and EMBASE databases from inception to 7 July 2023. Reporting Quality was evaluated based on a checklist with 31 items. The characteristics of studies and information for model construction and validation were extracted, summarized, and discussed. RESULTS: Eighteen studies (four prospective studies and fourteen retrospective studies with sample sizes of 14 to 772 patients and 2.7 to 93.1 samples per patient) were included in this study. Two-compartment models were the commonly used structural models for methotrexate, and the clearance range of methotrexate ranged from 2.32 to 19.03 L/h (median: 6.86 L/h). Body size and renal function were found to significantly affect the clearance of methotrexate for pediatric patients. There were limited reports on the role of other covariates, such as gene polymorphisms and co-medications, in the pharmacokinetic parameters of methotrexate pediatric patients. Internal and external evaluations were used to assess the performance of the population pharmacokinetic models. CONCLUSION: A more rigorous external evaluation needs to be performed before routine clinical use to select the appropriate PopPK model. Further research is necessary to incorporate larger cohorts or pool analyses in specific susceptible pediatric populations to improve the understanding of predicted exposure profiles and covariate identification.
Assuntos
Antimetabólitos Antineoplásicos , Metotrexato , Modelos Biológicos , Metotrexato/farmacocinética , Metotrexato/administração & dosagem , Humanos , Criança , Antimetabólitos Antineoplásicos/farmacocinética , Antimetabólitos Antineoplásicos/administração & dosagem , Antimetabólitos Antineoplásicos/uso terapêutico , Antimetabólitos Antineoplásicos/sangue , Adolescente , Neoplasias/tratamento farmacológicoRESUMO
Methotrexate (MTX) is an anticancer drug used for the treatment of various cancers and autoimmune diseases. In this study, High Performance Liquid Chromatography (HPLC) method was developed and validated for the estimation of MTX in rabbit plasma with high estimation rate and recovery. Various validation parameters like, sensitivity, sample recovery, accuracy and precision analysis were studied. The pre-saturated reversed C18 end capped HPLC column was used to separate MTX present in rabbit plasma. A solvent mixture of 100mM phosphate buffer pH 7.4 and acetonitrile (92:8 percent v/v) was employed as the mobile phase. Analysis was carried out at Ê max 303 nm and retention time of MTX was found 5.32 min. During the method development and validation ICHQ2 (R1) guidelines were strictly followed. Developed method was found excellent in terms of recovery of MTX from plasma samples (98.6%). It is obvious from the current study that the developed HPLC method can be utilized to analyze the level of MTX in patients. Furthermore, the cost of the developed method for the determination of MTX would be very low as compared to the previously reported methods.
Assuntos
Antimetabólitos Antineoplásicos/sangue , Metotrexato/sangue , Animais , Feminino , Masculino , Metotrexato/química , Estrutura Molecular , Coelhos , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
The adverse reactions caused by 6-thioguanine (6-TG) in anti-cancer treatment are closely related to the dose, leading to the urgent need for clinical monitoring of its concentration. In this work, a highly reproducible free-standing liquid membrane (FLM) surface-enhanced Raman spectroscopy (SERS) substrate was developed to detect 6-TG in human urine and serum quantitatively. Briefly, a prepared sample was adjusted to pH 2 and mixed with concentrated core-shell bimetallic nanoparticle (AgcoreAushell NP) suspension. The Au/Ag ratio of the AgcoreAushell NPs was optimized. Then the mixture was formed into an FLM using a custom mold. The relative standard deviation (RSD) of the experimental results can be stabilized below 10% (n ≥ 10). The R2 of the calibration curve in the range of 10 ~ 100 µg kg-1 was 0.988. In addition, the limit of detection (LOD) (3σ/k) of 6-TG was 5 µg kg-1. The FLM SERS platform has been successfully applied to the rapid and reliable analysis of 6-TG spiked in body fluids.
Assuntos
Antimetabólitos Antineoplásicos/sangue , Antimetabólitos Antineoplásicos/urina , Análise Espectral Raman/métodos , Tioguanina/sangue , Tioguanina/urina , Ouro/química , Humanos , Limite de Detecção , Nanopartículas Metálicas/química , Prata/químicaRESUMO
Retrospective data suggest that gastric acid reduction by proton pump inhibitors (PPIs) impairs the dissolution and subsequent absorption of capecitabine, and thus potentially reduces the capecitabine exposure. Therefore, we examined prospectively the effect of esomeprazole on the pharmacokinetics of capecitabine. In this randomized crossover study, patients with cancer were assigned to 2 sequence groups, each consisting of 3 phases: capecitabine with esomeprazole administration 3 hours before (phase A), capecitabine alone (phase B), and capecitabine concomitant with cola and esomeprazole co-administration 3 hours before (phase C). The primary end point was the relative difference (RD) in exposure to capecitabine assessed by the area under the plasma concentration-time curve from zero to infinity (AUC0-inf ) and analyzed by a linear mixed effect model. Twenty-two evaluable patients were included in the analysis. After esomeprazole, there was a 18.9% increase in AUC0-inf of capecitabine (95% confidence interval (CI) -10.0% to 57.0%, P = 0.36). In addition, capecitabine half-life was significantly longer after esomeprazole (median 0.63 hours vs. 0.46 hours, P = 0.005). Concomitant cola did not completely reverse the effects observed after esomeprazole (RD 3.3% (95% CI -16.3 to 27.4%, P = 1.00). Capecitabine exposure is not negatively influenced by esomeprazole cotreatment. Therefore, altered capecitabine pharmacokinetics do not explain the assumed worse clinical outcome of PPI-cotreated patients with cancer.
Assuntos
Antimetabólitos Antineoplásicos/farmacocinética , Capecitabina/farmacocinética , Esomeprazol/administração & dosagem , Neoplasias/tratamento farmacológico , Inibidores da Bomba de Prótons/administração & dosagem , Antimetabólitos Antineoplásicos/administração & dosagem , Antimetabólitos Antineoplásicos/sangue , Disponibilidade Biológica , Capecitabina/administração & dosagem , Capecitabina/sangue , Bebidas Gaseificadas , Estudos Cross-Over , Interações Medicamentosas , Monitoramento de Medicamentos , Esomeprazol/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/sangue , Neoplasias/diagnóstico , Países Baixos , Estudos Prospectivos , Inibidores da Bomba de Prótons/efeitos adversos , Resultado do TratamentoRESUMO
PURPOSE: High-dose methotrexate (HDMTX)-associated acute kidney injury with delayed MTX clearance has been linked to an excess in MTX-induced toxicities. Glucarpidase is a recombinant enzyme that rapidly hydrolyzes MTX into non-toxic metabolites. The recommended dose of glucarpidase is 50 U/kg, which has never been formally established in a dose finding study in humans. Few case reports, mostly in children, suggest that lower doses of glucarpidase might be equally effective in lowering MTX levels. METHODS: Seven patients with toxic MTX plasma concentrations following HDMTX therapy were treated with half-dose glucarpidase (mean 25 U/kg, range 17-32 U/kg). MTX levels were measured immunologically as well as by liquid chromatography-mass spectrometry (LC-MS). Toxicities were assessed according to National Cancer Institute-Common Terminology Criteria for Adverse Events (CTCAE) v5.0. RESULTS: All patients experienced HDMTX-associated kidney injury (median increase in creatinine levels within 48 h after HDMTX initiation compared to baseline of 251%, range 80-455%) and showed toxic MTX plasma concentrations (range 3.1-182.4 µmol/L) before glucarpidase injection. The drug was administered 42-70 h after HDMTX initiation. Within one day after glucarpidase injection, MTX plasma concentrations decreased by ≥ 97.7% translating into levels of 0.02-2.03 µmol/L. MTX rebound was detected in plasma 42-73 h after glucarpidase initiation, but concentrations remained consistent at < 10 µmol/L. CONCLUSION: Half-dose glucarpidase seems to be effective in lowering MTX levels to concentrations manageable with continued intensified folinic acid rescue.
Assuntos
Injúria Renal Aguda/tratamento farmacológico , Metotrexato/efeitos adversos , Metotrexato/sangue , gama-Glutamil Hidrolase/administração & dosagem , Injúria Renal Aguda/sangue , Injúria Renal Aguda/induzido quimicamente , Adulto , Idoso , Antimetabólitos Antineoplásicos/efeitos adversos , Antimetabólitos Antineoplásicos/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/uso terapêutico , Trombocitopenia/induzido quimicamente , gama-Glutamil Hidrolase/uso terapêuticoRESUMO
BACKGROUND AND OBJECTIVE: High-dose methotrexate (HD-MTX) is the mainstream therapy of current acute lymphoblastic leukemia (ALL) regimens, but frequent intra- and interindividual differences in the clinical response to HD-MTX lead to chemotherapeutic interruption or discontinuation. The exact mechanism of transport across the cell membrane and the disposition of active methotrexate metabolites-methotrexate polyglutamates (MTXPGs)-are not well described in the literature. The aim of this study was to gain more insight into the plasma distribution of methotrexate and MTXPGs in pediatric patients with ALL and to clarify the obscure pathways of MTXPGs. METHODS: We prospectively measured the concentrations of MTXPG1-7 in plasma samples from three male pediatric patients treated with HD-MTX and leucovorin rescue according to the IC-BFM 2009 protocol using liquid chromatography-mass spectrometry (LC-MS). Blood samples were obtained at 24, 36, 42, and 48 h after the start of HD-MTX treatment. RESULTS: Noticeable plasma concentrations of MTXPGs with a 2.2-fold interpatient variability were detected. The highest interindividual variability in total plasma MTXPG concentration was observed at 36 h, and ranged from 13.78 to 30.82 µmol/L. Among all patients, the predominant polyglutamate types in relation to the total plasma MTXPG concentration at each time point were MTXPG3 (16.71-30.02%) and MTXPG5 (26.23-38.60%), while MTXPG7 was the least abundant MTXPG (3.22-5.02%). CONCLUSION: The presence of MTXPGs in plasma of patients with ALL could be related to the action of ABC efflux transporters on blood cells and hepatocytes resulting from the administration of high doses of methotrexate. This study may not draw definitive conclusions, but it does reduce uncertainty about the dynamics of methotrexate and its active metabolites, which may be of vital importance for achieving a clinical response.
Assuntos
Antimetabólitos Antineoplásicos/farmacocinética , Metotrexato/farmacocinética , Ácido Poliglutâmico/farmacocinética , Antimetabólitos Antineoplásicos/administração & dosagem , Antimetabólitos Antineoplásicos/sangue , Criança , Cromatografia Líquida , Humanos , Masculino , Metotrexato/administração & dosagem , Metotrexato/sangue , Plasma/metabolismo , Ácido Poliglutâmico/administração & dosagem , Ácido Poliglutâmico/sangue , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Estudos ProspectivosRESUMO
BACKGROUND: High-dose methotrexate (HDMTX) is likely to cause a number of side effects and manifest itself as hepatotoxicity, nephrotoxicity, mucositis, and neurotoxicity. A several studies demonstrated the efficacy of extracorporeal detoxification methods such as plasma exchange, hemodialysis (HD), HD filtration, and hemoperfusion for the treatment of MTX delayed clearance. However, none of the existing methods as effective as expected and limited for general implementation due to a procedure-related complication. CASE REPORT: Here, we report a successful implementation of HA-230 hemoadsorption procedure to remove cumulated MTX from the body and reduce its toxicity in a child with ALL after high-dose chemotherapy. RESULTS AND CONCLUSION: Based on our results, single-hemoadsorption procedure with the HA-230 adsorber in case of delayed methotrexate clearance was safe and well-tolerated in a pediatric patient with ALL and would significantly improve the patient's condition. Further studies need to demonstrate its safety and efficacy in a large number of pediatric patients.
Assuntos
Antimetabólitos Antineoplásicos/isolamento & purificação , Antimetabólitos Antineoplásicos/toxicidade , Hemoperfusão , Metotrexato/isolamento & purificação , Metotrexato/toxicidade , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Antimetabólitos Antineoplásicos/administração & dosagem , Antimetabólitos Antineoplásicos/sangue , Criança , Hemoperfusão/métodos , Humanos , Metotrexato/administração & dosagem , Metotrexato/sangueRESUMO
PURPOSE: A simple, rapid and reliable method to quantify methotrexate (MTX) in human plasma by high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) was established and validated in two laboratories. PATIENTS AND METHODS: Sample separation was achieved on a Synergi Hydro-RP column (50 mm×2.0 mm, 2.5 µm) with a gradient elution program in 3.5 min after a simple protein precipitation with methanol (MeOH) and acetonitrile (ACN) (1:1). About 5 mM ammonium formate aqueous solution with 0.2% formic acid and ACN were used as mobile phase with a flow rate of 0.5 mL/min at 40 °C. Mass spectrometry detection using AB Sciex Triple Quad 4500 mass spectrometer (4500 QQQ) and Qtrap 5500 mass spectrometer (5500 Q-trap) were both characterized by electrospray ionization (ESI) for positive ions in multiple reaction-monitoring (MRM) mode. Quantitative ion pairs were m/z 455.1âm/z 308.0 for MTX and m/z 248.1âm/z 121.0 for tinidazole (TNZ) used as internal standard (IS). RESULTS: Linear calibration curves were generated over the range of 5-1000 ng/mL (r2> 0.99) on both the 4500 QQQ and 5500 Q-trap, both of the intra- and inter-batch precision were less than 7.67% and accuracy ranged from 96.33% to 108.94%. The recovery and matrix effect were 82.20-93.98% and 102.69-105.28%, respectively. CONCLUSION: An analytical method transfer was achieved by re-verification in two laboratories to ensure stability and reproducibility and this method has been applied for therapeutic drug monitoring (TDM) successfully in children and adults with NHL, and during routine TDM, two delayed elimination of MTX cases were observed and analyzed.
Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Linfoma não Hodgkin/tratamento farmacológico , Metotrexato/sangue , Espectrometria de Massas em Tandem/métodos , Adolescente , Adulto , Idoso , Antimetabólitos Antineoplásicos/administração & dosagem , Antimetabólitos Antineoplásicos/sangue , Criança , Pré-Escolar , Monitoramento de Medicamentos/métodos , Feminino , Humanos , Masculino , Metotrexato/administração & dosagem , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Espectrometria de Massas por Ionização por ElectrosprayRESUMO
BACKGROUND The impact of therapeutic drug management (TDM) on reducing toxicity and improving efficacy in colorectal cancer (CRC) patients receiving fluorouracil-based chemotherapy is still unclear. MATERIAL AND METHODS A total of 207 patients (Study Group n=54, Historical Group n=153) with metastatic colorectal cancer were enrolled. All of them received 6 administrations of the 5-FU based regimens. Initial 5-FU dosing of all patients was calculated using body surface area (BSA). In the Study Group, individual exposure during each cycle was measured using a nanoparticle immunoassay, and the 5-FU blood concentration was calculated using the area under the curve (AUC). We adjusted the 5-FU infusion dose of the next cycle based on the AUC data of the previous cycle to achieve the target of 20-30 mg×h/L. RESULTS In the fourth cycle, patients in the target concentration range (AUC mean, 26.3 mg×h/L; Median, 28 mg×h/L; Range, 14-38 mg×h/L; CV, 22.4%) accounted for 46.8% of all patients, which were more than the ones in the first cycle (P<0.001). 5-FU TDM significantly reduced the toxicity of chemotherapy and improved its efficacy. The Study Group (30/289) showed a lower percentage of severe adverse events than that in the Historical Group (185/447) (P<0.001). The incidences of complete response and partial response in the Study Group were higher than those in the Historical Group (P=0.032). CONCLUSIONS TDM in colorectal cancer can reduce toxicity, improve efficacy and clinical outcome, and can be routinely used in 5-FU-based chemotherapy.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias Colorretais , Monitoramento de Medicamentos/métodos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Fluoruracila , Metástase Neoplásica , Idoso , Antimetabólitos Antineoplásicos/administração & dosagem , Antimetabólitos Antineoplásicos/efeitos adversos , Antimetabólitos Antineoplásicos/sangue , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Área Sob a Curva , China/epidemiologia , Neoplasias Colorretais/sangue , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/epidemiologia , Neoplasias Colorretais/patologia , Cálculos da Dosagem de Medicamento , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/diagnóstico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/etiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/prevenção & controle , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/efeitos adversos , Fluoruracila/sangue , Humanos , Masculino , Conduta do Tratamento Medicamentoso/estatística & dados numéricos , Metástase Neoplásica/patologia , Metástase Neoplásica/terapia , Estadiamento de Neoplasias , Risco Ajustado/métodos , Resultado do TratamentoRESUMO
WHAT IS KNOWN AND OBJECTIVE: Methotrexate (MTX) is an important agent for the treatment of primary central nervous system lymphomas (PCNSL) but needs to be given in big doses by intravenous infusions to achieve therapeutic concentrations in the cerebrospinal fluid. However, co-administration with many drugs may delay the excretion of MTX which may cause serious adverse effects if the serum concentration exceeds 0.1 µmol/L 72 h after an intravenous infusion. CASE SUMMARY: A 67-year-old Japanese female with PCNSL was treated with high-dose MTX-based chemotherapy. The serum MTX concentration 72 h post-infusion was 0.153 µmol/L when she was taking levofloxacin (LVFX) but <0.1 µmol/L 72 h after 4 subsequent infusions when she was not taking LVFX. She was given many other drugs but the timing of the short course of LVFX and the fact that ciprofloxacin also delays MTX excretion suggests that LVFX was the cause. WHAT IS NEW AND CONCLUSION: Co-administration of LVFX may delay the excretion of MTX. Therefore, serum concentrations of MTX should be monitored to help prevent and improve the management of potentially serious MTX drug-drug interaction.
Assuntos
Antibacterianos/farmacologia , Antimetabólitos Antineoplásicos/farmacocinética , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Levofloxacino/farmacologia , Linfoma/tratamento farmacológico , Metotrexato/farmacocinética , Idoso , Antimetabólitos Antineoplásicos/administração & dosagem , Antimetabólitos Antineoplásicos/sangue , Antimetabólitos Antineoplásicos/uso terapêutico , Relação Dose-Resposta a Droga , Interações Medicamentosas , Feminino , Humanos , Metotrexato/administração & dosagem , Metotrexato/sangue , Metotrexato/uso terapêuticoRESUMO
PURPOSE: The clinical application of gemcitabine (GEM) is limited by its pharmacokinetic properties. The aim of this study was to characterize the stability in circulating plasma, tumor targeting, and payload release of liposome-encapsulated GEM, FF-10832. METHODS: Antitumor activity was assessed in xenograft mouse models of human pancreatic cancer. The pharmacokinetics of GEM and its active metabolite dFdCTP were also evaluated. RESULTS: In mice with Capan-1 tumors, the dose-normalized areas under the curve (AUCs) after FF-10832 administration in plasma and tumor were 672 and 1047 times higher, respectively, than after using unencapsulated GEM. The tumor-to-bone marrow AUC ratio of dFdCTP was approximately eight times higher after FF-10832 administration than after GEM administration. These results indicated that liposomal encapsulation produced long-term stability in circulating plasma and tumor-selective targeting of GEM. In mice with Capan-1, SUIT-2, and BxPC-3 tumors, FF-10832 had better antitumor activity and tolerability than GEM. Internalization of FF-10832 in tumor-associated macrophages (TAMs) was revealed by flow cytometry and confocal laser scanning microscopy, and GEM was efficiently released from isolated macrophages of mice treated with FF-10832. These results suggest that TAMs are one of the potential reservoirs of GEM in tumors. CONCLUSION: This study found that FF-10832 had favorable pharmacokinetic properties. The liposomal formulation was more effective and tolerable than unencapsulated GEM in mouse xenograft tumor models. Hence, FF-10832 is a promising candidate for the treatment of pancreatic cancer.
Assuntos
Antimetabólitos Antineoplásicos/sangue , Desoxicitidina/análogos & derivados , Composição de Medicamentos/métodos , Sistemas de Liberação de Medicamentos/métodos , Neoplasias Pancreáticas/sangue , Ensaios Antitumorais Modelo de Xenoenxerto/métodos , Animais , Antimetabólitos Antineoplásicos/administração & dosagem , Antimetabólitos Antineoplásicos/síntese química , Linhagem Celular Tumoral , Desoxicitidina/administração & dosagem , Desoxicitidina/sangue , Desoxicitidina/síntese química , Estabilidade de Medicamentos , Feminino , Humanos , Lipossomos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos ICR , Camundongos Nus , Neoplasias Pancreáticas/tratamento farmacológico , Resultado do Tratamento , GencitabinaRESUMO
High-dose methotrexate (HDMTX) is an important component of treatment in pediatric acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LL). Optimal rescue therapy is essential for the safe administration of HDMTX. A cost-effective strategy that does not compromise safety is necessary for low- and middle-income countries. Consecutive admissions for HDMTX in children with ALL and LL over 12 months were analyzed. The dose of HDMTX was 3 g/m2 in B-ALL and B-LL and 5 g/m2 in T-ALL and T-LL. A methotrexate level was measured at 42 hours of starting HDMTX infusion (T42-MTX). Three doses of folinic acid at T42, T48, and T54 and alkalinized hydration till T54 were administered if T42-MTX <1 µM. A total of 282 cycles of HDMTX that were administered in 71 patients were analyzed. T42-MTX was <1 µM in 266 (94.3%) cycles. T42-MTX was ≥1 µM in 12% and 3% of cycles of HDMTX administered at a dose of 5 g/m2 and 3 g/m2, respectively (p = .074). The median duration of hospitalization for HDM was three days and did not differ with the dose of HDMTX administered (p = .427). Mucositis, delayed recovery of blood counts, and hospitalization for reversible toxicity occurred after 21 (7.4%), 28 (9.9%), and 19 (6.7%) cycles of HDMTX, respectively. Mucositis was greater following the administration of 5 g/m2 of HDMTX. A single T42-MTX measurement permits the safe administration of HDMTX and an expedited discharge from the hospital within three days in more than 90% of children with ALL/LL.
Assuntos
Antimetabólitos Antineoplásicos/uso terapêutico , Metotrexato/uso terapêutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Adolescente , Antimetabólitos Antineoplásicos/administração & dosagem , Antimetabólitos Antineoplásicos/efeitos adversos , Antimetabólitos Antineoplásicos/sangue , Criança , Pré-Escolar , Monitoramento de Medicamentos , Feminino , Humanos , Lactente , Masculino , Metotrexato/administração & dosagem , Metotrexato/efeitos adversos , Metotrexato/sangue , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamento farmacológico , Estudos RetrospectivosRESUMO
OBJECTIVE: This study investigated the relationships of tumor status (stage, renal involvement, bone marrow status, bulky disease, liver function), tumor gene polymorphism, and methotrexate (MTX) dosage (stratified by treatment group) with blood MTX levels and adverse reactions (ADR). METHODS: We retrospectively reviewed 63 mature B cell lymphoma patients who were treated in our center. Genotyping of the MTHFR 677 and SLCO1B1 genes was carried out, and the relationships between tumor status, polymorphism of the genes, MTX level, and ADR were analyzed. RESULTS: Altogether, 63 children were included. The mean blood MTX concentration was 0.25 ± 0.2 umol/L at 45 h. Liver dysfunction and bulky disease were both correlated with MTX level (both P < 0.05). ADRs were higher among patients with blood MTX > 0.5 mmol/l at 45 h than for the groups with lower blood MTX. The MTHFR 677 CT genotype was correlated with liver function damage (P = 0.04); the rs11045879 locus CC genotype of SLCO1B1, stage IV, and bulky disease at the time of diagnosis were correlated with 4° neutropenia (P < 0.05). Stage IV, bulky disease, leukemia stage at the time of diagnosis, and C2 treatment group were correlated with severe anemia (P < 0.05). Stage IV, bulky disease, leukemia stage, renal invasion at the time of diagnosis, and C2 treatment group were associated with severe thrombocytopenia (P < 0.05). Bulky disease and renal invasion at the time of diagnosis were associated with severe mucositis and severe infection (P < 0.05). CONCLUSION: Taken together, our data demonstrate that gene polymorphism, MTX levels, tumor status, and treatment group might be useful to optimize MTX therapy and estimate toxicity.
Assuntos
Antimetabólitos Antineoplásicos/sangue , Transportador 1 de Ânion Orgânico Específico do Fígado/genética , Linfoma de Células B/patologia , Metotrexato/sangue , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Adolescente , Anemia/induzido quimicamente , Antimetabólitos Antineoplásicos/administração & dosagem , Antimetabólitos Antineoplásicos/efeitos adversos , Medula Óssea/patologia , Doença Hepática Induzida por Substâncias e Drogas/genética , Criança , Pré-Escolar , China , Feminino , Genótipo , Humanos , Lactente , Fígado/fisiopatologia , Linfoma de Células B/sangue , Linfoma de Células B/tratamento farmacológico , Masculino , Metotrexato/administração & dosagem , Metotrexato/efeitos adversos , Estadiamento de Neoplasias , Neutropenia/induzido quimicamente , Neutropenia/genética , Polimorfismo de Nucleotídeo Único , Estudos Retrospectivos , Estomatite/induzido quimicamente , Trombocitopenia/induzido quimicamenteRESUMO
Combination therapy of tegafur/uracil (UFT) and leucovorin (LV) is widely used to treat colorectal cancers. Although this therapy has a significant therapeutic effect, severe adverse effects occur frequently. Therapeutic drug monitoring (TDM) may help to prevent adverse effects. A useful assay that can quantitate plasma levels of 5-FU, uracil, and tegafur simultaneously for TDM has been desired, but such a method is not currently available. In this study, we aimed to develop a sensitive method for simultaneous quantification of 5-FU, uracil, and tegafur in human plasma using ultra-performance liquid chromatography coupled to tandem mass spectrometry (UPLC-MS/MS). After preparing plasma samples by protein precipitation and liquid extraction, 5-FU, uracil, and tegafur were analyzed by UPLC-MS/MS in negative electrospray ionization mode. Validation was performed according to US Food and Drugs Administration guidance. The calibration curves were linear over concentration ranges of 2-500 ng/mL for 5-FU, 20-5000 ng/mL for uracil, and 200-50,000 ng/mL for tegafur. The corresponding average recovery rates were 79.9, 80.9, and 87.8%. The method provides accuracy within 11.6% and precision below 13.3% for all three analytes. Matrix effects of 5-FU, uracil, and tegafur were higher than 43.5, 84.9, and 100.2%, respectively. This assay was successfully applied to assess the time courses of plasma 5-FU, uracil, and tegafur concentrations in two patients with colorectal liver metastasis who received UFT/LV therapy after hepatectomy. In conclusion, we succeeded to develop a sensitive and robust UPLC-MS/MS method for simultaneous quantification of 5-FU, uracil, and tegafur in human plasma. This method is potentially useful for TDM in patients receiving UFT/LV combination therapy.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Cromatografia Líquida de Alta Pressão/normas , Monitoramento de Medicamentos/métodos , Fluoruracila/sangue , Espectrometria de Massas em Tandem/normas , Tegafur/sangue , Uracila/sangue , Antimetabólitos Antineoplásicos/sangue , Calibragem , Cromatografia Líquida de Alta Pressão/métodos , Neoplasias Colorretais/sangue , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Hepatectomia/métodos , Humanos , Leucovorina/uso terapêutico , Fígado/patologia , Fígado/cirurgia , Neoplasias Hepáticas/sangue , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/cirurgia , Sensibilidade e Especificidade , Espectrometria de Massas em Tandem/métodosRESUMO
High-dose methotrexate (HD-MTX) therapy is widely used in patients with acute lymphoblastic leukemia (ALL) and lymphoma. However, some patients experience delayed MTX elimination, which requires treatment suspension or dose reduction to avoid organ damage. This single-center retrospective analysis reviewed the clinical data of 88 children with ALL or non-Hodgkin lymphoma who received a total of 269 courses of HD-MTX therapy between April 2008 and April 2019. HD-MTX was defined as MTX administration at 2.0, 3.0, or 5.0 g/m2 over a 24-h period, and delayed MTX elimination was defined as a serum MTX concentration ≥ 1.0 µmol/L at 48 h after the start of HD-MTX. Clinical factors were compared between courses with and without delayed MTX elimination. MTX elimination was delayed in 21 of the 269 courses (7.8%). Multivariate analysis showed that first HD-MTX course (OR 4.04), lower urine volume per BSA on the first day of HD-MTX administration (< 2,675 mL/m2, OR 5.10), higher total bilirubin (> 0.5 mg/dL, OR 5.11), lower eGFR (< 136 mL/min/1.73 m2, OR 3.90), higher dose of MTX(> 3.0 g/m2, OR 10.8), and lower urine volume per BSA on the next day of starting HD-MTX (< 2,107 mL/m2, OR 3.43) were independent risk factors for delayed MTX elimination.
Assuntos
Antimetabólitos Antineoplásicos/uso terapêutico , Metotrexato/uso terapêutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Antimetabólitos Antineoplásicos/administração & dosagem , Antimetabólitos Antineoplásicos/sangue , Criança , Humanos , Metotrexato/administração & dosagem , Metotrexato/sangue , Leucemia-Linfoma Linfoblástico de Células Precursoras/sangue , Eliminação Renal , Estudos Retrospectivos , Fatores de RiscoRESUMO
A retrospective, single-center, observational study evaluated the difference in time to clearance of high-dose methotrexate between the fluorescence polarization immunoassay (FPIA) and ARK methotrexate assay in pediatric hematology/oncology patients. The post-ARK immunoassay group had an increase in clearance time of 33 h/cycle and 31% increase in cycles with delayed clearance. On posthoc analysis, use of an adjusted clearance threshold of <0.15 µmol/L post-ARK immunoassay, as opposed to the traditional <0.1 µmol/L threshold, would have similar incidence of delayed clearance. The ARK immunoassay demonstrated a positive bias compared to the FPIA in clinical practice, which led to an institutional policy change.
Assuntos
Antimetabólitos Antineoplásicos/sangue , Imunoensaio de Fluorescência por Polarização/métodos , Neoplasias Hematológicas/tratamento farmacológico , Imunoensaio/métodos , Metotrexato/sangue , Adolescente , Antimetabólitos Antineoplásicos/administração & dosagem , Criança , Relação Dose-Resposta a Droga , Feminino , Seguimentos , Neoplasias Hematológicas/sangue , Neoplasias Hematológicas/patologia , Humanos , Masculino , Metotrexato/administração & dosagem , Monitorização Fisiológica , Prognóstico , Estudos RetrospectivosRESUMO
Polymorphisms in methotrexate transporter pathways have been associated with methotrexate toxicities and clearance. Recent genome-wide association studies have revealed that the SLCO1B1 T521C variant is associated with methotrexate elimination. We present a case of a pediatric patient with acute lymphoblastic leukemia who suffered from persistently high plasma methotrexate concentrations and acute kidney injuries after the admin-istration of a medium dose of methotrexate. Subsequent genetic analysis showed that he was a carrier of dys-functional genetic variants associated with methotrexate clearance. This case highlights that polymorphisms of methotrexate transporter pathways can adversely affect methotrexate elimination in a clinically significant manner.
Assuntos
Antimetabólitos Antineoplásicos/farmacocinética , Metotrexato/farmacocinética , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Antimetabólitos Antineoplásicos/administração & dosagem , Antimetabólitos Antineoplásicos/sangue , Criança , Humanos , Transportador 1 de Ânion Orgânico Específico do Fígado , Masculino , Metotrexato/administração & dosagem , Metotrexato/sangue , Metilenotetra-Hidrofolato Redutase (NADPH2) , Polimorfismo de Nucleotídeo Único/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genéticaRESUMO
PURPOSE: Precise and timely detection of methotrexate (MTX) concentration played a key role in high-dose MTX individualization therapy in acute lymphoblastic leukemia (ALL) children to avoid serious adverse effects or nonresponse. This report described a sensibility and validation of ultra-high performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) method for therapeutic drug monitoring (TDM) of methotrexate concentration in children's plasma. METHODS: One-step protein precipitation of samples was accomplished by adding 200 µL of acetonitrile to 100 µL of plasma sample. The separation of plasma samples was carried out on a ZORBAX Eclipse Plus C18 Rapid Resolution HD column with gradient elution using a mobile phase constituted of acetonitrile and 1% formic acid. The detection was executed by electrospray ionization (ESI) of triple quadrupole tandem mass spectrometer (TQMS) in the multiple reaction monitoring (MRM) mode with the transitions m/z 455.2 â 307.9 for methotrexate and m/z 458.2 â 311.2 for IS, separately. Linear concentration range of the calibration curve was 44-11,000 nmol/L and 44 nmol/L was the lower limit of quantification. RESULTS: The methotrexate elution time was at 1.577 min, and the overall running time was only 3.3 min. The intra- and interday precision for all the analysis results was within 11.24%, and mean recoveries rate of methotrexate exceeded 87.98%. CONCLUSION: The described and fully validated UHPLC-MS/MS method was successfully applied in clinical TDM after infusion of high-dose methotrexate 1-5 g/m2 to 41 childpatients.
Assuntos
Antimetabólitos Antineoplásicos/uso terapêutico , Monitoramento de Medicamentos , Metotrexato/uso terapêutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Adolescente , Antimetabólitos Antineoplásicos/sangue , Antimetabólitos Antineoplásicos/química , Calibragem , Criança , Pré-Escolar , Cromatografia Líquida de Alta Pressão , Humanos , Metotrexato/sangue , Metotrexato/química , Estrutura Molecular , Garantia da Qualidade dos Cuidados de Saúde , Espectrometria de Massas em TandemRESUMO
PURPOSE: Hyperammonemia is an important adverse event associated with 5-fluorouracil (5FU) from 5FU metabolite accumulation. We present a case of an advanced gastric cancer patient with chronic renal failure, who was treated with 5FU/leucovorin (LV) infusion chemotherapy (2-h infusion of LV and 5FU bolus followed by 46-h 5FU continuous infusion on day 1; repeated every 2 weeks) and developed hyperammonemia, with the aim of exploring an appropriate hemodialysis (HD) schedule to resolve its symptoms. METHODS: The blood concentrations of 5FU and its metabolites, α-fluoro-ß-alanine (FBAL), and monofluoroacetate (FA) of a patient who had hyperammonemia from seven courses of palliative 5FU/LV therapy for gastric cancer were measured by liquid chromatography-mass spectrometry. RESULTS: On the third day of the first cycle, the patient presented with symptomatic hyperammonemia relieved by emergency HD. Thereafter, the 5FU dose was reduced; however, in cycles 2-4, the patient developed symptomatic hyperammonemia and underwent HD on day 3 for hyperammonemia management. In cycles 5-7, the timing of scheduled HD administration was changed from day 3 to day 2, preventing symptomatic hyperammonemia. The maximum ammonia and 5FU metabolite levels were significantly lower in cycles 5-7 than in cycles 2-4 (NH3 75 ± 38 vs 303 ± 119 µg/dL, FBAL 13.7 ± 2.5 vs 19.7 ± 2.0 µg/mL, FA 204.0 ± 91.6 vs 395.9 ± 12.6 ng/mL, mean ± standard deviation, all p < 0.05). After seven cycles, partial response was confirmed. CONCLUSION: HD on day 2 instead of 3 may prevent hyperammonemia in 5FU/LV therapy.