RESUMEN
BACKGROUND: After High-Dose Methotrexate (HD-MTX), folinic acid rescue therapy (Leucovorin) is administered to reduce side effects in pediatric acute lymphoblastic leukemia (ALL) patients. Leucovorin and MTX are structural analogues, possibly competing for cellular transport and intracellular metabolism. We hypothesize that Leucovorin accumulates during consecutive courses, which might result in a lower MTX uptake. METHODS: We prospectively measured red blood cell (RBC) folate and MTX levels during four HD-MTX and Leucovorin courses in 43 patients treated according the DCOG ALL-11 protocol with 2-weekly HD-MTX (5 g/m2/dose) and Leucovorin (15 mg/m2/dose) using LC-MS/MS. We estimated a linear mixed model to assess the relationship between these variables over time. RESULTS: Both RBC MTX-PG and folate levels increased significantly during protocol M. MTX-PG2-5 levels increased most substantially after the first two HD-MTX courses (until median 113.0 nmol/L, IQR 76.8-165.2) after which levels plateaued during the 3d and 4th course (until median 141.3 nmol/L, IQR 100.2-190.2). In parallel, folate levels increased most substantially after the first two HD-MTX courses (until median 401.6 nmol/L, IQR 163.3-594.2) after which levels plateaued during the 3d and 4th course (until median 411.5 nmol/L, IQR 240.3-665.6). The ratio folate/MTX-PG decreased significantly over time, which was mostly due to the relatively higher increase (delta) of MTX-PG. CONCLUSION: These results suggest that the increase in RBC folate levels does not seem to have a large effect on RBC MTX levels. Future studies, assessing competition of Leucovorin and MTX on other cellular mechanisms which might negatively affect treatment efficacy, are necessary.
Asunto(s)
Ácido Fólico/sangre , Metotrexato/sangre , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Adolescente , Antimetabolitos Antineoplásicos/administración & dosificación , Antimetabolitos Antineoplásicos/sangre , Niño , Preescolar , Cromatografía Liquida , Eritrocitos/efectos de los fármacos , Femenino , Humanos , Lactante , Leucovorina/administración & dosificación , Leucovorina/sangre , Masculino , Metotrexato/administración & dosificación , Leucemia-Linfoma Linfoblástico de Células Precursoras/sangre , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Espectrometría de Masas en Tándem , Resultado del TratamientoRESUMEN
Delayed elimination of plasma methotrexate (MTX), which leads to elevated toxicity, is often observed in patients receiving high-dose methotrexate (HD-MTX) therapy, despite of the preventive measures. In this study, we investigated the factors that delay elimination of plasma MTX in patients on HD-MTX therapy. Fifteen patients who received HD-MTX therapy (21 cycles) were classified into two groups: delayed elimination of plasma MTX (38.1%, 8/21) and normal elimination of plasma MTX (61.9%, 13/21). Patient characteristics, plasma MTX concentrations, laboratory values, and adverse reactions were compared between the two groups using Fisher's exact test. Univariate analysis showed that co-administration of calcium channel blockers was significantly associated with delayed elimination of plasma MTX (p = 0.042). This is the first report demonstrating that co-administration of calcium channel blockers may be a predictive factor of delayed elimination of plasma MTX in patients receiving HD-MTX therapy.
Asunto(s)
Antimetabolitos Antineoplásicos/farmacocinética , Bloqueadores de los Canales de Calcio/administración & dosificación , Metotrexato/farmacocinética , Adulto , Anciano , Antimetabolitos Antineoplásicos/administración & dosificación , Antimetabolitos Antineoplásicos/sangre , Interacciones Farmacológicas , Femenino , Humanos , Linfoma/tratamiento farmacológico , Masculino , Metotrexato/administración & dosificación , Metotrexato/sangre , Persona de Mediana Edad , Estudios RetrospectivosRESUMEN
Methotrexate (MTX) is a folic acid antagonist that is widely used as an immunosuppressant and chemotherapeutic agent. After high-dose administration of MTX serum levels must be monitored to determine when to administer leucovorin, a folic acid analog that bypasses the enzyme inhibition caused by MTX and reverses its toxicity. We describe a rapid and simple turbulent flow liquid chromatography (TFLC) method implementing positive heated electrospray ionization (HESI) for the accurate and precise determination of MTX, 7-hydroxymethotrexate (7-OH MTX), and 4-amino-4-deoxy-N(10)-methylpteroic acid (DAMPA) concentrations in serum. MTX is isolated from serum samples (100 µL) after protein precipitation with a methanolic solution containing internal standard (MTX-D3) followed by centrifugation. The supernatant is injected into the turbulent flow liquid chromatography which is followed by electrospray positive ionization tandem mass spectrometry (TFLC-ESI-MS/MS) and quantified using a six-point calibration curve. For MTX, 7-OH MTX, and DAMPA the assays were linear from 20 to 1000 nmol/L. Dilutions of 10-, 100-, and 1000-fold were validated giving a clinically reportable range of 20 to 1.0 × 10(6) nmol/L. Within-day and between-day precisions at concentrations spanning the analytical measurement ranges were less than 10 % for all three analytes.
Asunto(s)
Antimetabolitos Antineoplásicos/sangre , Inmunosupresores/sangre , Metotrexato/análogos & derivados , Metotrexato/sangre , Espectrometría de Masas en Tándem/métodos , Antimetabolitos Antineoplásicos/metabolismo , Cromatografía Líquida de Alta Presión/métodos , Cromatografía Liquida/métodos , Monitoreo de Drogas/métodos , Humanos , Inmunosupresores/metabolismo , Metotrexato/metabolismo , Espectrometría de Masa por Ionización de Electrospray/métodosRESUMEN
INTRODUCTION: 5-Fluoro-2'-deoxycytidine (FdCyd; NSC48006), a fluoropyrimidine nucleoside inhibitor of DNA methylation, is degraded by cytidine deaminase (CD). Pharmacokinetic evaluation was carried out in cynomolgus monkeys in support of an ongoing phase I study of the PO combination of FdCyd and the CD inhibitor tetrahydrouridine (THU; NSC112907). METHODS: Animals were dosed intravenously (IV) or per os (PO). Plasma samples were analyzed by LC-MS/MS for FdCyd, metabolites, and THU. Clinical chemistry and hematology were performed at various times after dosing. A pilot pharmacokinetic study was performed in humans to assess FdCyd bioavailability. RESULTS: After IV FdCyd and THU administration, FdCyd C(max) and AUC increased with dose. FdCyd half-life ranged between 22 and 56 min, and clearance was approximately 15 mL/min/kg. FdCyd PO bioavailability after THU ranged between 9 and 25 % and increased with increasing THU dose. PO bioavailability of THU was less than 5 %, but did result in plasma concentrations associated with inhibition of its target CD. Human pilot studies showed comparable bioavailability for FdCyd (10 %) and THU (4.1 %). CONCLUSION: Administration of THU with FdCyd increased the exposure to FdCyd and improved PO FdCyd bioavailability from <1 to 24 %. Concentrations of THU and FdCyd achieved after PO administration are associated with CD inhibition and hypomethylation, respectively. The schedule currently studied in phase I studies of PO FdCyd and THU is daily times three at the beginning of the first and second weeks of a 28-day cycle.
Asunto(s)
Antimetabolitos Antineoplásicos/farmacocinética , Citidina Desaminasa/antagonistas & inhibidores , Desoxicitidina/análogos & derivados , Inhibidores Enzimáticos/farmacocinética , Tetrahidrouridina/farmacocinética , Administración Oral , Animales , Antimetabolitos Antineoplásicos/administración & dosificación , Antimetabolitos Antineoplásicos/sangre , Disponibilidad Biológica , Biotransformación , Estudios de Cohortes , Desoxicitidina/administración & dosificación , Desoxicitidina/sangre , Desoxicitidina/farmacocinética , Relación Dosis-Respuesta a Droga , Combinación de Medicamentos , Evaluación Preclínica de Medicamentos , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/sangre , Femenino , Semivida , Humanos , Infusiones Intravenosas , Macaca fascicularis , Masculino , Tasa de Depuración Metabólica , Proyectos Piloto , Tetrahidrouridina/administración & dosificación , Tetrahidrouridina/sangreAsunto(s)
Adenocarcinoma/tratamiento farmacológico , Antimetabolitos Antineoplásicos/administración & dosificación , Desoxicitidina/análogos & derivados , Neoplasias Duodenales/tratamiento farmacológico , Fluorouracilo/análogos & derivados , Terapia Neoadyuvante/métodos , Neoplasias Pancreáticas/tratamiento farmacológico , Adenocarcinoma/cirugía , Anciano , Antimetabolitos Antineoplásicos/sangre , Antimetabolitos Antineoplásicos/metabolismo , Capecitabina , Quimioterapia Adyuvante , Desoxicitidina/administración & dosificación , Desoxicitidina/metabolismo , Esquema de Medicación , Neoplasias Duodenales/cirugía , Femenino , Fluorouracilo/administración & dosificación , Fluorouracilo/metabolismo , Humanos , Masculino , Persona de Mediana Edad , Neoplasias Pancreáticas/cirugía , PancreaticoduodenectomíaRESUMEN
In situ coating of 5-fluorouracil pellets by ethylcellulose and pectin powder mixture (8:3 weight ratio) in capsule at simulated gastrointestinal media provides colon-specific drug release in vitro. This study probes into pharmacodynamic and pharmacokinetic profiles of intra-capsular pellets coated in vivo in rats with reference to their site-specific drug release outcomes. The pellets were prepared by extrusion-spheronization technique. In vitro drug content, drug release, in vivo pharmacokinetics, local colonic drug content, tumor, aberrant crypt foci, systemic hematology and clinical chemistry profiles of coated and uncoated pellets were examined against unprocessed drug. In vivo pellet coating led to reduced drug bioavailability and enhanced drug accumulation at colon (179.13 µg 5-FU/g rat colon content vs 4.66 µg/g of conventional in vitro film-coated pellets at 15 mg/kg dose). The in vivo coated pellets reduced tumor number and size, through reforming tubular epithelium with basement membrane and restricting expression of cancer from adenoma to adenocarcinoma. Unlike uncoated pellets and unprocessed drug, the coated pellets eliminated aberrant crypt foci which represented a putative preneoplastic lesion in colon cancer. They did not inflict additional systemic toxicity. In vivo pellet coating to orally target 5-fluorouracil delivery at cancerous colon is a feasible therapeutic treatment approach.
Asunto(s)
Focos de Criptas Aberrantes/tratamiento farmacológico , Adenocarcinoma/tratamiento farmacológico , Adenoma/tratamiento farmacológico , Antimetabolitos Antineoplásicos/administración & dosificación , Neoplasias del Colon/tratamiento farmacológico , Fluorouracilo/administración & dosificación , Focos de Criptas Aberrantes/inducido químicamente , Focos de Criptas Aberrantes/metabolismo , Focos de Criptas Aberrantes/patología , Adenocarcinoma/inducido químicamente , Adenocarcinoma/metabolismo , Adenocarcinoma/patología , Adenoma/inducido químicamente , Adenoma/metabolismo , Adenoma/patología , Administración Oral , Animales , Antimetabolitos Antineoplásicos/sangre , Antimetabolitos Antineoplásicos/química , Antimetabolitos Antineoplásicos/farmacocinética , Disponibilidad Biológica , Celulosa/análogos & derivados , Celulosa/química , Química Farmacéutica , Neoplasias del Colon/inducido químicamente , Neoplasias del Colon/metabolismo , Neoplasias del Colon/patología , Dimetilhidrazinas , Sistemas de Liberación de Medicamentos , Estudios de Factibilidad , Femenino , Fluorouracilo/sangre , Fluorouracilo/química , Fluorouracilo/farmacocinética , Pectinas/química , Polvos , Ratas Sprague-Dawley , Solubilidad , Comprimidos Recubiertos , Tecnología Farmacéutica/métodos , Carga Tumoral/efectos de los fármacosRESUMEN
STUDY OBJECTIVE: Because the incidence rate of renal impairment is 2-10% for patients treated with high-dose methotrexate and renal impairment develops in 0-12.4% of patients treated for osteosarcoma, we sought to evaluate the efficacy of glucarpidase, a recently approved drug that rapidly hydrolyzes methotrexate to inactive metabolites, which allows for nonrenal clearance in patients with delayed renal methotrexate elimination. DESIGN: Pooled analysis of efficacy data from four multicenter single-arm compassionate-use clinical trials using protocols from 1993 to 2007. PATIENTS: Of 476 patients with renal toxicity and delayed methotrexate elimination who were treated with intravenous glucarpidase for rescue after high-dose methotrexate, 169 patients had at least one preglucarpidase (baseline) plasma methotrexate concentration greater than 1 µmol/L and one postglucarpidase methotrexate concentration measurement by high-performance liquid chromatography and were included in the efficacy analysis; renal recovery was assessed in 436 patients who had at least one recorded preglucarpidase and postglucarpidase serum creatinine concentration measurement. MEASUREMENTS AND MAIN RESULTS: Efficacy was defined as rapid and sustained clinically important reduction (RSCIR) in plasma methotrexate concentration, with a concentration of 1 µmol/L or lower at all postglucarpidase determinations. Median age of efficacy-evaluable patients was 20 years (range 5 weeks-84 years). Osteosarcoma (36%), non-Hodgkin lymphoma (27%), and acute lymphoblastic leukemia (20%) were the most frequent underlying diagnoses. Median preglucarpidase serum methotrexate was 11.7 µmol/L. At the first (median 15 minutes) through the last (median 40 hours) postglucarpidase measurement, plasma methotrexate concentrations demonstrated consistent 99% median reduction. RSCIR was achieved by 83 (59%) of 140 patients. A total of 64% of patients with renal impairment greater than or equal to Common Terminology Criteria for Adverse Events grade 2 recovered to grade 0 or 1 at a median of 12.5 days after glucarpidase administration. CONCLUSION: Glucarpidase caused a clinically important 99% or greater sustained reduction of serum methotrexate levels and provided noninvasive rescue from methotrexate toxicity in renally impaired patients.
Asunto(s)
Lesión Renal Aguda/prevención & control , Antimetabolitos Antineoplásicos/uso terapéutico , Metotrexato/uso terapéutico , gamma-Glutamil Hidrolasa/uso terapéutico , Lesión Renal Aguda/sangre , Lesión Renal Aguda/inducido químicamente , Antimetabolitos Antineoplásicos/administración & dosificación , Antimetabolitos Antineoplásicos/efectos adversos , Antimetabolitos Antineoplásicos/sangre , Neoplasias Óseas/sangre , Neoplasias Óseas/complicaciones , Neoplasias Óseas/tratamiento farmacológico , Ensayos de Uso Compasivo , Esquema de Medicación , Humanos , Leucovorina/administración & dosificación , Leucovorina/uso terapéutico , Metotrexato/administración & dosificación , Metotrexato/efectos adversos , Metotrexato/sangre , Osteosarcoma/sangre , Osteosarcoma/complicaciones , Osteosarcoma/tratamiento farmacológico , Resultado del Tratamiento , gamma-Glutamil Hidrolasa/administración & dosificaciónRESUMEN
The method of combined neoadjuvant treatment of resectable cancer recti, consisting of preoperative radiaton therapy, using big-fractionized intensive irradiation on the endolymphatic chemotherapy background together with fluorouracil with following surgical intervention (main group), in terms up to 72 h, was elaborated in the clinic. The patients, to whom the chemotherapy and radiation therapy were conducted, were included into control groups. Postoperative complications have had occurred in 8 (12.5%) patients of the main group and in 10 (15.87%) and 13 (14.29%)--in control groups. The five-year survival indices in the main group have constituted (73.5 +/- 6.3)%, and in control groups--(64.6 +/- 5.8) and (64.4 +/- 6.8)%. The local recurrence rate in the main group have constituted (6.2 +/- 3.0)%, and of the remote metastatizing--(15.6 +/- 4.5)%.
Asunto(s)
Antimetabolitos Antineoplásicos/uso terapéutico , Quimioradioterapia Adyuvante/métodos , Neoplasias del Colon/cirugía , Fluorouracilo/uso terapéutico , Terapia Neoadyuvante/métodos , Antimetabolitos Antineoplásicos/administración & dosificación , Antimetabolitos Antineoplásicos/sangre , Neoplasias del Colon/epidemiología , Neoplasias del Colon/patología , Neoplasias del Colon/terapia , Supervivencia sin Enfermedad , Fluorouracilo/administración & dosificación , Fluorouracilo/sangre , Humanos , Leucovorina/administración & dosificación , Leucovorina/uso terapéutico , Metástasis de la Neoplasia , Recurrencia Local de Neoplasia/epidemiología , Recurrencia Local de Neoplasia/prevención & controlRESUMEN
We present a case of toxicity caused by a drug interaction between capecitabine and phenytoin (PHT). The drug combination elevated the plasma level of PHT in a patient on chemotherapy with capecitabine for colorectal cancer. Our patient was a 44-year-old woman diagnosed with epilepsy in her 20's, being treated with valproic acid (VPA) and PHT. Adjuvant chemotherapy with capecitabine began following surgery for colorectal cancer. Seven weeks later, she developed numbness, dizziness, dysarthria and difficulty walking, and was hospitalized for investigation. Her serum PHT level was elevated at 35. 1 µg/ mL. This case suggests that when capecitabine and PHT are coadministered, PHT levels should be monitored frequently, and that PHT dosage should be adjusted accordingly if it cannot be replaced by an alternative anticonvulsant.
Asunto(s)
Anticonvulsivantes/efectos adversos , Antimetabolitos Antineoplásicos/efectos adversos , Neoplasias Colorrectales/tratamiento farmacológico , Desoxicitidina/análogos & derivados , Epilepsia/tratamiento farmacológico , Fluorouracilo/análogos & derivados , Fenitoína/efectos adversos , Adulto , Anticonvulsivantes/sangre , Anticonvulsivantes/uso terapéutico , Antimetabolitos Antineoplásicos/sangre , Antimetabolitos Antineoplásicos/uso terapéutico , Capecitabina , Neoplasias Colorrectales/sangre , Neoplasias Colorrectales/complicaciones , Desoxicitidina/efectos adversos , Desoxicitidina/sangre , Desoxicitidina/uso terapéutico , Interacciones Farmacológicas , Epilepsia/sangre , Epilepsia/complicaciones , Femenino , Fluorouracilo/efectos adversos , Fluorouracilo/sangre , Fluorouracilo/uso terapéutico , Humanos , Fenitoína/sangre , Fenitoína/uso terapéuticoRESUMEN
The management of high-dose methotrexate (MTX) therapy in patients with cancer depends on the routine monitoring of drug exposures in conjunction with leucovorin (LV), urine pH, patient hydration, and other clinical indices of patient well-being. A key factor in patient oversight is the facilitation of MTX clearance to minimize drug-related toxicity. The aim of this investigation was to evaluate the performance of a clinical decision support system and Bayesian forecasting algorithm in the prediction of MTX concentrations and assessment of LV dosing requirements in pediatric and young adult patients with cancer based on the current practice at the Children's Hospital of Philadelphia. Fifty patients ranging in age from 8 months to 21 years (weight range, 7.6-163.3 kg) contributing 80 total dosing events (183 MTX serum concentrations) were studied. The forecasting model was able to consistently predict future MTX concentrations with the knowledge of one prior concentration and continued to improve with additional concentration data made available through daily therapeutic drug monitoring. Precision was good at 12.9% with low bias at 2.2%. Comparison between the decision support system recommendations for LV rescue relative to the actual LV administration was also made. Sixteen patients would have initiated rescue therapy earlier, seven patients would have received a larger dose (42 smaller), and LV would have been given less often for 37 patients. The forecasting algorithm in the MTX dashboard was reasonably accurate in predicting MTX concentrations and should improve further as the underlying model and prediction algorithm evolves. This decision support system can be useful in helping physicians decide if a patient is clearing MTX as expected or if more aggressive rescue therapy is warranted.
Asunto(s)
Antimetabolitos Antineoplásicos/farmacocinética , Sistemas de Apoyo a Decisiones Clínicas , Monitoreo de Drogas , Leucovorina/farmacocinética , Metotrexato/farmacocinética , Neoplasias/tratamiento farmacológico , Adolescente , Adulto , Antimetabolitos Antineoplásicos/efectos adversos , Antimetabolitos Antineoplásicos/sangre , Antimetabolitos Antineoplásicos/uso terapéutico , Teorema de Bayes , Niño , Preescolar , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Lactante , Leucovorina/efectos adversos , Leucovorina/uso terapéutico , Masculino , Metotrexato/efectos adversos , Metotrexato/sangre , Metotrexato/uso terapéutico , Neoplasias/metabolismo , Programas Informáticos , Nivel de Atención , Adulto JovenRESUMEN
PURPOSE: To describe the successful use of glucarpidase (carboxypeptidase G2) in the treatment of high-dose methotrexate-induced nephrotoxicity in a patient with osteosarcoma. SUMMARY: A 12-year-old female patient who had been diagnosed with low-grade right mandibular osteosarcoma was started on a protocol of cisplatin plus doxorubicin alternating with high-dose methotrexate. Following her first dose of methotrexte, she developed acute renal failure and higher than expected 24h methotrexate level of 478µM/L. High-dose leucovorin rescue was started with vigorous hydra- tion and urine alkalinization together with two sessions of hemodialysis. Because her methotrexate level was persistently high, the investigational drug glucarpidase was administered. Methotrexate level dropped from 65 to 16.3 µM/L after a single dose of glucarpidase measured by fluorescence polarization immunoassay. Leucovorin and urine alkalinization were continued until day 17 when the patient's kidney function normalized and methotrexate level reached 0.05 µM/L. The patient tolerated glucarpidase well without any significant adverse events. CONCLUSION: Glucarpidase is a safe and effective agent in the management of high-dose methotrexate-induced nephrotoxicity and delayed methotrexate elimination.
Asunto(s)
Lesión Renal Aguda/inducido químicamente , Lesión Renal Aguda/tratamiento farmacológico , Antimetabolitos Antineoplásicos/efectos adversos , Drogas en Investigación/uso terapéutico , Metotrexato/efectos adversos , Osteosarcoma/tratamiento farmacológico , gamma-Glutamil Hidrolasa/uso terapéutico , Lesión Renal Aguda/sangre , Antimetabolitos Antineoplásicos/administración & dosificación , Antimetabolitos Antineoplásicos/sangre , Niño , Quimioterapia Combinada , Terapia Enzimática , Femenino , Humanos , Jordania , Leucovorina/uso terapéutico , Neoplasias Mandibulares/tratamiento farmacológico , Metotrexato/administración & dosificación , Metotrexato/sangre , Resultado del Tratamiento , Complejo Vitamínico B/uso terapéuticoAsunto(s)
Antimetabolitos Antineoplásicos/administración & dosificación , Quimioterapia Adyuvante/métodos , Neoplasias Colorrectales/tratamiento farmacológico , Relación Dosis-Respuesta a Droga , Fluorouracilo/administración & dosificación , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Antimetabolitos Antineoplásicos/sangre , Antimetabolitos Antineoplásicos/toxicidad , Área Bajo la Curva , Ensayos Clínicos como Asunto , Ensayos de Selección de Medicamentos Antitumorales/métodos , Fluorouracilo/sangre , Fluorouracilo/toxicidad , Humanos , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
When methotrexate (MTX) salvage chemotherapy is performed for primary brain malignant lymphoma, use of leucovonrin rescue must often be extended due to delays in the degradation of blood concentration. We examined whether delay in MTX blood concentration degradation could be prevented by chai-ling-tang (Sairei-to) which has diuretic action. In the five cases examined were MTX blood concentration 72 hours after MTX administration was more than 1 x 10(-7) M. A single dose of 3 g of chai-ling-tang was administered three times on the day the MTX salvage chemotherapy was subsequently performed. MTX blood concentration at 72 hours post MTX administration and subsequent chai-ling-tang administration was less than 1 x 10(-7) M in all five cases. In addition, urea nitrogen and creatinine levels in serum increased and creatinine clearance decreased following MTX administration, however these changes induced by MTX administration were reduced by chai-ling-tang administration. Chai-ling-tang was effective in preventing an MTX deferent delay in MTX high-dose therapy by improving renal blood flow.
Asunto(s)
Antimetabolitos Antineoplásicos/administración & dosificación , Antimetabolitos Antineoplásicos/sangre , Neoplasias Encefálicas/tratamiento farmacológico , Diuréticos/farmacología , Medicamentos Herbarios Chinos/farmacología , Linfoma/tratamiento farmacológico , Metotrexato/administración & dosificación , Metotrexato/sangre , Anciano , Anciano de 80 o más Años , Antimetabolitos Antineoplásicos/farmacocinética , Nitrógeno de la Urea Sanguínea , Creatinina/sangre , Femenino , Humanos , Masculino , Metotrexato/farmacocinética , Persona de Mediana Edad , Terapia RecuperativaRESUMEN
Intravenous methotrexate therapy with subsequent calcium folinate rescue is widely used for treatment of various neoplastic diseases, both in adults and in children. The optimization of the methotrexate dose and/or the calcium folinate rescue is based on pharmacokinetic data calculated from plasma concentrations collected after cessation of the methotrexate infusion. The aim of the present study was to evaluate the possibility of substituting capillary blood samples with blood samples drawn from central venous catheters (PORT-A-CATH) for therapeutic drug monitoring of methotrexate on the pediatric oncology ward. Nine cancer patients (4 females and 5 males; median age: 15 years; range: 5-20 years) were included. The quantitative analysis of methotrexate was carried out by fluorescence polarization immunoassay (FPIA). The concentrations of methotrexate in venous and capillary samples were closely correlated (rs = 0.98; P < 0.0001; n = 71). The venous/capillary plasma concentration ratio was 1.00 [median value; interquartile range (IQR): 0.882-1.094]; for 85% of the data points the ratio was 0.8 to 1.2, independent of drug concentration. The observed plasma concentration differences in blood samples drawn from central venous accesses and obtained from capillary blood samples in this study could have altered the calcium folinate rescue at 1 treatment occasion only. Plotting all measured methotrexate concentration time data for the individual patients during the elimination phase, on a chart including a normal elimination curve, is mandatory to enable proper handling of the subsequent rescue after high-dose methotrexate therapy. Blood sampling from the central venous access can be used only under certain circumstances for therapeutic drug monitoring of methotrexate. Carefully evaluated standardized instructions regarding rinsing, flushing, and discarding waste volumes, as well as precautions to minimize the required blood volume, are needed.
Asunto(s)
Antimetabolitos Antineoplásicos/sangre , Recolección de Muestras de Sangre/métodos , Cateterismo Venoso Central , Dedos/irrigación sanguínea , Metotrexato/sangre , Adolescente , Adulto , Antimetabolitos Antineoplásicos/administración & dosificación , Antimetabolitos Antineoplásicos/uso terapéutico , Capilares , Niño , Preescolar , Monitoreo de Drogas , Femenino , Inmunoensayo de Polarización Fluorescente , Humanos , Masculino , Metotrexato/administración & dosificación , Metotrexato/uso terapéutico , Neoplasias/tratamiento farmacológico , Servicio de Oncología en Hospital , PediatríaRESUMEN
We studied the pharmacokinetics of 5-FU after S-1 oral administration at the usual dose (80 mg/m2) for adjuvant chemotherapy in 13 advanced gastric cancer patients (Stage II, III), and at a decreased dose (60 mg/m2) for adjuvant or combined chemotherapy in 13 advanced gastric cancer patients. Pharmacokinetic parameters of 5-FU in the serum were as follows: Cmax, 159 .9 2+/-45.2 ng/mL, Tmax, 2.17+/-0.58 h;T1/2, 3.13+/-2.88 h; and AUC(0-8), 768.0+/-260.8 ng h/mL in the patients with the usual dose, and Cmax, 117.3+/-55.1 ng/mL; Tmax, 2.62+/-0.9 6 h; T1/2, 3.09+/-1.9 5 h and AUC(0-8), 565.9+/-216.8 ng h/mL in the patients with the decreased dose. No difference in AUC was observed between operative methods. Adverse events of more than grade 3 were recognized in 7 patients, and AUC of 6 patients were more than 800 ng h/mL. The plasma concentration of 5-FU was quite different between patients. The difference of Cmax and AUC was 3-4 times. It was concluded that we must pay attention to individual differences in the plasma concentration of 5-FU in postoperative gastric cancer patients when S-1 would be administered.
Asunto(s)
Antimetabolitos Antineoplásicos/administración & dosificación , Fluorouracilo/farmacocinética , Gastrectomía , Ácido Oxónico/administración & dosificación , Neoplasias Gástricas/sangre , Neoplasias Gástricas/tratamiento farmacológico , Tegafur/administración & dosificación , Administración Oral , Anciano , Antimetabolitos Antineoplásicos/sangre , Quimioterapia Adyuvante , Combinación de Medicamentos , Femenino , Gastrectomía/métodos , Humanos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Neoplasias Gástricas/patología , Neoplasias Gástricas/cirugíaRESUMEN
A high-performance liquid chromatography (HPLC) system using a porous graphitic carbon (PGC) stationary phase interfaced with an electrospray ionization (ESI) source and a tandem mass spectrometer (MS/MS) for the analysis of cytarabine (ara-C) in mouse plasma samples has been developed in support of a pharmacodynamic study. The graphitized carbon column was adopted for the separation of ara-C and endogenous peaks from mouse plasma samples under the reversed-phase phase mode in liquid chromatography. The retention characteristics of the PGC column and the ionization efficiencies of all analytes based on the experimental factors such as the composition of mobile phases were investigated. The potential of ionization suppression resulting from the endogenous biological matrices on the PGC column during HPLC/ESI-MS/MS was investigated using post-column infusion. The concentrations of ara-C in mouse plasma obtained by using PGC-HPLC/MS/MS and ion-pairing HPLC/MS/MS were found to be in good agreement in terms of analytical accuracy.
Asunto(s)
Antimetabolitos Antineoplásicos/farmacocinética , Cromatografía Líquida de Alta Presión/instrumentación , Citarabina/farmacocinética , Grafito/química , Espectrometría de Masa por Ionización de Electrospray , Animales , Antimetabolitos Antineoplásicos/sangre , Cromatografía Líquida de Alta Presión/métodos , Citarabina/sangre , Evaluación Preclínica de Medicamentos , Inyecciones Intraperitoneales , Ratones , Espectrometría de Masas en TándemRESUMEN
N-Nicotinoyl-2-(5-fluorouracil-1-yl)-D,L-glycine (NFG) methyl-(NFGM), ethyl-(NFGE) and isopropyl esters (NFGIp) were synthesized and their potential as a prodrug of 5-fluorouracil (5-FU) for rectal administration was investigated. Chemical conversion proceeded either by elimination of (5-FU) or by hydrolysis of ester group. 5-FU was released from NFGIp, NFGE and NFGM 90.5%, 71.3% and 48.5% of the dose, respectively, in 80% human plasma and 79.8%, 56.3% and 31.6%, respectively, in pH 7.4 buffer solution after 48 h of incubation at 37 degrees C. Release of 5-FU occurred mainly from NFG esters but very slightly from NFG, which suggested that release of 5-FU was greatly dependent on the stability of the ester group against hydrolysis. Solubility (M) in pH 7.4 buffer solution was 0.13, 0.09 and 0.04 and apparent partition coefficient in 1-octanol/pH 7.4 buffer solution was 0.76, 1.61 and 4.2, respectively, for NFGM, NFGE and NFGIp, which were in the ranges suitable for rectal absorption. Plasma concentration (microg/mL) of NFGM, NFGE and NFGIp at 50 min after rectal administration to rats was 1.9, 4.6 and 6.7, respectively, and that for 5-FU was below the limit of detection. Their potential as prodrugs of 5-FU for rectal administration is suggested.
Asunto(s)
Antimetabolitos Antineoplásicos/síntesis química , Fluorouracilo/síntesis química , Glicina/síntesis química , Profármacos/síntesis química , Administración Rectal , Animales , Antimetabolitos Antineoplásicos/administración & dosificación , Antimetabolitos Antineoplásicos/sangre , Antimetabolitos Antineoplásicos/farmacocinética , Disponibilidad Biológica , Tampones (Química) , Química Farmacéutica , Estabilidad de Medicamentos , Enema , Fluorouracilo/administración & dosificación , Fluorouracilo/análogos & derivados , Fluorouracilo/sangre , Fluorouracilo/farmacocinética , Glicina/administración & dosificación , Glicina/análogos & derivados , Glicina/sangre , Glicina/farmacocinética , Humanos , Concentración de Iones de Hidrógeno , Hidrólisis , Masculino , Estructura Molecular , Profármacos/administración & dosificación , Profármacos/farmacocinética , Ratas , Ratas Sprague-Dawley , Solubilidad , Tecnología FarmacéuticaRESUMEN
Aberrant DNA methylation patterns resulting in gene transcriptional repression are observed in numerous cancers. Decitabine, a DNA methyltransferase inhibitor, is being clinically evaluated in patients with hematologic malignancies and solid tumors. Decitabine is rather unstable and decomposes to 1-beta-D-2'-deoxyribofuranosyl-3-guanylurea under basic conditions and several additional unknown products under neutral conditions. This has greatly limited application of pharmacokinetic assays to clinical development of decitabine. In this paper, a high-performance liquid chromatography/ultraviolet multi-stage mass spectrometry (HPLC-UV-MSn) study of the decomposition of decitabine in water and human plasma revealed that these previously unknown products are isomers of the intermediates formyl-1-beta-D-2'-deoxyribofuranosyl-3-guanylurea and 1-beta-D-2'-deoxyribofuranosyl-3-guanylurea. A HPLC tandem mass spectrometry (MS/MS) method for the determination of decitabine concentrations in human and rat plasma has been developed. This method was based on a specific fragmentation pathway of the molecular ion of decitabine at m/z 229 to generate a unique fragment ion at m/z 113 under collision-induced dissociation. Separation of decitabine and the stable internal standard dihydro-5-aza-cytidine from the endogenous interfering substance in plasma extract was carried out on a C18 Aquasil column under an isocratic elution with a mobile phase consisting of 5% water/acetonitrile and 10 mM ammonium formate. The detection of decitabine was via selected reaction monitoring (SRM, 229 > 113), and its ionization was enhanced by post-column addition of acetonitrile. Effects of sample preparation and handling parameters on the stability of decitabine were also evaluated in human plasma at various temperatures. The accuracy and precision of this assay showed a coefficient of variation of <15% over the range of 0.5-25 ng for rat plasma and 0.1-25 ng for human plasma injected on-column. Pharmacokinetics of decitabine in rats following intravenous doses of 1.0 and 5.0 mg/kg were characterized. In the rat, plasma concentration-time profiles were found to follow a biexponential decline and the pharmacokinetics was dose-independent. Application of this decitabine pharmacokinetic assay to human studies is therefore justified and ongoing.
Asunto(s)
Azacitidina/análogos & derivados , Análisis Químico de la Sangre/métodos , Cromatografía Líquida de Alta Presión/métodos , Espectrometría de Masa por Ionización de Electrospray/métodos , Espectrofotometría Ultravioleta/métodos , Animales , Antimetabolitos Antineoplásicos/administración & dosificación , Antimetabolitos Antineoplásicos/sangre , Antimetabolitos Antineoplásicos/farmacocinética , Azacitidina/administración & dosificación , Azacitidina/sangre , Azacitidina/farmacocinética , Decitabina , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos/métodos , Humanos , Masculino , Tasa de Depuración Metabólica , Ratas , Ratas Sprague-DawleyRESUMEN
PURPOSE: This phase I study was conducted to determine the toxicities, pharmacokinetics, and recommended doses of pemetrexed in cancer patients with normal and impaired renal function. PATIENTS AND METHODS: Patients received a 10-minute infusion of 150 to 600 mg/m2 of pemetrexed every 3 weeks. Patients were stratified for independent dose escalation by measured glomerular filtration rate (GFR) into four cohorts ranging from > or = 80 to less than 20 mL/min. Pemetrexed plasma and urine pharmacokinetics were evaluated for the first cycle. Patients enrolled after December 1999 were supplemented with oral folic acid and intramuscular vitamin B12. RESULTS: Forty-seven patients were treated with 167 cycles of pemetrexed. Hematologic dose-limiting toxicities occurred in vitamin-supplemented patients (two; 15%) and non-supplemented patients (six; 18%), and included febrile neutropenia (four patients) and grade 4 thrombocytopenia (two patients). Nonhematologic toxicities included fatigue, diarrhea, and nausea, and did not correlate with renal function. Accrual was discontinued in patients with GFR less than 30 mL/min after one patient with a GFR of 19 mL/min died as a result of treatment-related toxicities. Pemetrexed plasma clearance positively correlated with GFR (r2 = 0.736), resulting in increased drug exposures in patients with impaired renal function. With vitamin supplementation, pemetrexed 600 mg/m2 was tolerated by patients with a GFR > or = 80 mL/min, whereas patients with a GFR of 40 to 79 mL/min tolerated a dose of 500 mg/m2. CONCLUSION: Pemetrexed was well tolerated at doses of 500 mg/m2 with vitamin supplementation in patients with GFR > or = 40 mL/min. Additional studies are needed to define appropriate dosing for renally impaired patients receiving higher dose pemetrexed with vitamin supplementation.
Asunto(s)
Antimetabolitos Antineoplásicos/administración & dosificación , Antimetabolitos Antineoplásicos/farmacocinética , Glutamatos/administración & dosificación , Glutamatos/farmacocinética , Guanina/análogos & derivados , Fallo Renal Crónico/complicaciones , Fallo Renal Crónico/metabolismo , Neoplasias/complicaciones , Neoplasias/tratamiento farmacológico , Adulto , Anciano , Antimetabolitos Antineoplásicos/efectos adversos , Antimetabolitos Antineoplásicos/sangre , Antimetabolitos Antineoplásicos/orina , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Diarrea/inducido químicamente , Esquema de Medicación , Fatiga/inducido químicamente , Femenino , Ácido Fólico/administración & dosificación , Glutamatos/efectos adversos , Glutamatos/sangre , Glutamatos/orina , Guanina/administración & dosificación , Guanina/efectos adversos , Guanina/sangre , Guanina/farmacocinética , Guanina/orina , Humanos , Fallo Renal Crónico/sangre , Fallo Renal Crónico/orina , Masculino , Persona de Mediana Edad , Náusea/inducido químicamente , Neutropenia/inducido químicamente , Pemetrexed , Trombocitopenia/inducido químicamente , Vitamina B 12/administración & dosificaciónRESUMEN
PURPOSE: To evaluate the effects of liposomal chemotherapeutic agent, nanoparticle size, and liposome circulation time on tissue coagulation and intratumoral drug uptake when radiofrequency (RF) ablation is combined with adjuvant intravenous liposomal chemotherapy in an animal breast tumor model. MATERIALS AND METHODS: Ninety-one R3230 mammary adenocarcinoma nodules were implanted in 48 Fischer rats. First, standardized RF ablation was combined with intravenous liposomal doxorubicin, cisplatin, or 5-fluorouracil (35 tumors each). Second, three different-sized doxorubicin-containing nanoparticle preparations were combined with standardized RF ablation. Last, two doxorubicin-containing liposome preparations with different blood elimination half-lives were combined with RF ablation. Coagulation diameter and interstitial doxorubicin concentration were measured 48 hours after treatment and compared with use of statistical analysis. RESULTS: All combinations of RF with liposomal chemotherapy caused significantly greater tumor necrosis than RF alone (P<.05). Significantly increased necrosis was observed with intravenous liposomal RF/doxorubicin and RF/cisplatin compared with intravenous liposomal RF/5-fluorouracil (P<.01). Greater coagulation was observed with RF combined with 100-nm nanoparticles compared with 20-nm or 250-nm nanoparticles (P=.01 and P=.04, respectively). Additionally, greater intratumoral doxorubicin uptake was observed in the group treated with 20-nm nanoparticles compared with those treated with other sizes of nanoparticles (P<.05). RF plus liposomal doxorubicin produced greater coagulation and intratumoral doxorubicin uptake than RF plus 1,2-dipalmitoyl-sn-glycero-3-phosphatidic acid (P<.05). CONCLUSION: When combined with RF ablation, modification of adjuvant intravenous liposomal chemotherapy, including nanoparticle size, circulation time, and chemotherapeutic agent, can influence intratumoral drug accumulation and tissue coagulation.