RESUMEN
The study described here was designed to investigate the influence of the hydration schedule of cisplatin on the pharmacokinetics of topotecan. To test this hypothesis, 13 adult cancer patients were treated with intravenous (i.v.) cisplatin followed by i.v. topotecan for 5 days every 3 weeks using a short hydration schedule (SHS) for cisplatin in the first course and a hyper-hydration schedule (HHS) in the second course or vice versa. Topotecan pharmacokinetic analysis was performed in plasma, whole blood and red blood cells in both courses on days 1, 2 and 5. 11 patients received both courses and were pharmacokinetically evaluable. No significant differences between the two studied schedules were noted in the clearances of topotecan on day 1 in the different matrices. However, in both hydration schedules, on average, slightly lower topotecan clearances were observed on both days 2 and 5 compared with day 1 in all of the matrices, while no differences were noted between days 2 and 5. This alteration was independent of the schedule used and was less pronounced than that which has been initially reported for SHS and, overall, will not have clinical consequences.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Cisplatino/farmacología , Neoplasias/tratamiento farmacológico , Topotecan/farmacocinética , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Cisplatino/administración & dosificación , Esquema de Medicación , Interacciones Farmacológicas , Femenino , Humanos , Infusiones Intravenosas , Masculino , Persona de Mediana Edad , Topotecan/administración & dosificaciónRESUMEN
The pharmacokinetic behaviour of anticancer drugs may be altered with aging due to (for example) differences in body composition and decreased hepatic and renal function. To address this issue for paclitaxel, we studied the pharmacokinetics of the drug in eight elderly women (>or=70 years) with metastatic breast cancer (median age (range), 77 years (70-84 years)) and a control group of 15 patients aged <70 years (median age (range), 54 years (22-69 years)). Paclitaxel was administered as a 1-h intravenous (i.v.) infusion at a dose of 80 (elderly) or 100 mg/m(2) (<70 years), and serial blood samples were obtained at baseline, and up to 24 h after the end of infusion. Paclitaxel concentration-time profiles were fitted to a linear three-compartment model without any demonstration of saturable behaviour. The clearance of unbound paclitaxel was 124+/-35.0 (elderly) versus 247+/-55.4 l/h/m(2) (<70 years) (P=0.002), and was inversely related to the patient's age (R(2)=0.857; P<0.00001). Total plasma clearance of the formulation vehicle Cremophor EL (CrEL) was 150+/-60.7 (elderly) versus 115+/-39.2 ml/h/m(2) (<70 years) (P=0.04). These data indicate an approximately 50% change in total body clearance of unbound paclitaxel and a concomitant significant increase in systemic exposure with age, most likely as a result of altered CrEL disposition. The clinical relevance of these observations with respect to toxicity profiles and antitumour efficacy requires further evaluation.
Asunto(s)
Antineoplásicos Fitogénicos/farmacocinética , Neoplasias de la Mama/metabolismo , Paclitaxel/farmacocinética , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Antineoplásicos Fitogénicos/administración & dosificación , Neoplasias de la Mama/tratamiento farmacológico , Estudios de Casos y Controles , Femenino , Humanos , Infusiones Intravenosas , Persona de Mediana Edad , Metástasis de la Neoplasia , Paclitaxel/administración & dosificación , Polietilenglicoles/administración & dosificación , Polietilenglicoles/farmacocinéticaRESUMEN
The aims of the study were twofold: (1) to evaluate the effect of food on the relative oral bioavailability of topotecan gelatin capsules in patients with solid tumours, and (2) to determine the absolute bioavailability of oral topotecan with reference to the intravenous (i.v.) formulation. The study had a randomized two-period cross-over design. On day 1 of the first treatment course patients were administered 2.3 mg m(-2) day(-1) of oral topotecan with or without a high-fat breakfast. They crossed over to receive the alternate regimen on day 2. In the second course (3 weeks later) fasted patients received topotecan orally (2.3 mg m(-2) day(-1)) or i.v. (1.5 mg m(-3) day). They crossed over to receive the alternate regimen on day 2. On days 3-5 of both treatment courses patients received oral topotecan. Plasma pharmacokinetics were performed on days 1 and 2 of the first and second course using a high-performance liquid chromatographic assay. Eighteen patients were enrolled in the study. The ratio of the area under the curve to infinity during fasted and high-fat treatment was 0.93+/-0.23 (90% confidence interval (CI) 0.83-1.03). Maximal plasma concentrations of topotecan were similar after ingestion of the capsules with (10.6+/-4.4 ng ml(-1)) or without food (9.2+/-4.1 ng ml(-1)) (P = 0.130). The time needed to reach maximal plasma levels was significantly prolonged after food intake (median 3.1 h, range 2.8-6.1) compared to fasted conditions (2.0 h, range 1.1-8.1) (P = 0.013). The absolute bioavailability of topotecan averaged 42+/-13% (90% CI 37-47%). The apparent terminal half-life was significantly longer after administration of oral topotecan (3.9+/-1.0 h) than after i.v. administration (2.7+/-0.4 h) (P < 0.001). Topotecan demonstrates suitable bioavailability for oral treatment. Co-administration of the topotecan gelatin capsules with a high-fat breakfast leads to a small decrease in absorption rate but does not affect the extent of absorption.
Asunto(s)
Antineoplásicos/farmacocinética , Topotecan/farmacocinética , Administración Oral , Adulto , Anciano , Disponibilidad Biológica , Estudios Cruzados , Femenino , Alimentos , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Sensitive high-performance liquid chromatographic (HPLC) methods have been developed and validated for the simultaneous determination of the antitumor drug topotecan and its metabolite N-desmethyltopotecan in human plasma, urine and faeces. Both compounds are reversibly hydrolysed to their hydroxycarboxylate forms at physiologic pH. Separate HPLC systems have been developed for the determination of lactone and total (lactone plus hydroxycarboxylate forms) concentrations in plasma. The instability of the analytes in plasma requires immediate protein precipitation with ice-cold methanol. The lactone forms of the analytes were stable in the methanol extracts for at least 15 months when stored at -70 degrees C. For the determination of the total levels, the plasma extracts were acidified with 25 mM phosphoric acid to convert the compounds into their lactone forms quantitatively. The sample pretreatment procedure for urine included dilution in methanol while the faecal samples were homogenized in distilled water and then extracted twice with an acetonitrile-ammonium acetate mixture. Separation was achieved on reversed-phase columns (Zorbax SB-C18) and detection was performed fluorimetrically at 380/527 nm. Within-run and between-run precisions were less than 10% and average accuracies were between 90 and 110%. The methods were used in a mass balance study in patients with malignant solid tumors to determine the disposition and routes of elimination of topotecan and N-desmethyltopotecan.
Asunto(s)
Antineoplásicos/farmacocinética , Cromatografía Líquida de Alta Presión/métodos , Heces/química , Topotecan/análogos & derivados , Topotecan/farmacocinética , Antineoplásicos/sangre , Antineoplásicos/orina , Calibración , Humanos , Neoplasias/sangre , Neoplasias/orina , Reproducibilidad de los Resultados , Espectrometría de Fluorescencia , Topotecan/sangre , Topotecan/orinaRESUMEN
During topotecan analysis of clinical urine samples, an additional peak eluting just after the solvent front was observed. This potential metabolite was isolated by chromatographic methods. Mass spectrometry data along with chromatographic retention data and fluorescence characteristics showed that the isolated fractions contained two compounds, i.e. topotecan-O-glucuronide and N-desmethyl topotecan-O-glucuronide. The concentrations of the metabolites in human urine were relatively low. When topotecan was given as a 30 min infusion at a dosage of 1.5 mg/m2 daily for five consecutive days every 3 weeks, the maximal metabolite concentrations in a 24 h urine sample were approximately 10% of topotecan-O-glucuronide and 3.5% of N-desmethyl topotecan-O-glucuronide with respect to the concentration of topotecan in the urine. This is the first report demonstrating that glucuronide metabolites of topotecan are present in the urine of treated patients.
Asunto(s)
Antineoplásicos/orina , Glucuronatos/orina , Topotecan/análogos & derivados , Topotecan/orina , Antineoplásicos/química , Antineoplásicos/uso terapéutico , Femenino , Glucuronatos/química , Humanos , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/orina , Topotecan/química , Topotecan/uso terapéuticoRESUMEN
We performed a phase I and pharmacological study to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT) of a cytotoxic regimen of the novel topoisomerase I inhibitor topotecan in combination with the topoisomerase II inhibitor etoposide, and to investigate the clinical pharmacology of both compounds. Patients with advanced solid tumours were treated at 4-week intervals, receiving topotecan intravenously over 30 min on days 1-5 followed by etoposide given orally twice daily on days 6-12. Topotecan-etoposide dose levels were escalated from 0.5/20 to 1.0/20, 1.0/40, and 1.25/40 (mg m-2 day-1)/(mg bid). After encountering DLT, additional patients were treated at 3-week intervals with the topotecan dose decreased by one level to 1.0 mg m-2 and etoposide administration prolonged from 7 to 10 days to allow further dose intensification. Of 30 patients entered, 29 were assessable for toxicity in the first course and 24 for response. The DLT was neutropenia. At doses of topotecan-etoposide 1.25/40 (mg m-2)/(mg bid) two out of six patients developed neutropenia grade IV that lasted more than 7 days. Reduction of the treatment interval to 3 weeks and prolonging etoposide dosing to 10 days did not permit further dose intensification, as a time delay to retreatment owing to unrecovered bone marrow rapidly emerged as the DLT. Post-infusion total plasma levels of topotecan declined in a biphasic manner with a terminal half-life of 2.1 +/- 0.3 h. Total body clearance was 13.8 +/- 2.7 l h-1 m-2 with a steady-state volume of distribution of 36.7 +/- 6.2 l m-2. N-desmethyltopotecan, a metabolite of topotecan, was detectable in plasma and urine. Mean maximal concentrations ranged from 0.23 to 0.53 nmol l-1, and were reached at 3.4 +/- 1.0 h after infusion. Maximal etoposide plasma concentrations of 0.75 +/- 0.54 and 1.23 +/- 0.57 micromol l-1 were reached at 2.4 +/- 1.2 and 2.3 +/- 1.0 h after ingestion of 20 and 40 mg respectively. The topotecan area under the plasma concentration vs time curve (AUC) correlated with the percentage decrease in white blood cells (WBC) (r2 = 0.70) and absolute neutrophil count (ANC) (r2 = 0.65). A partial response was observed in a patient with metastatic ovarian carcinoma. A total of 64% of the patients had stable disease for at least 4 months. The recommended dose for use in phase II clinical trials is topotecan 1.0 mg m-2 on days 1-5 and etoposide 40 mg bid on days 6-12 every 4 weeks.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Neoplasias/tratamiento farmacológico , Administración Oral , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Esquema de Medicación , Etopósido/administración & dosificación , Femenino , Enfermedades Hematológicas/inducido químicamente , Humanos , Infusiones Intravenosas , Masculino , Persona de Mediana Edad , Neoplasias/metabolismo , Topotecan/administración & dosificaciónRESUMEN
A sensitive high-performance liquid chromatography (HPLC) method for the determination of topotecan and total levels of topotecan (lactone plus its ring-opened hydroxycarboxylate form) was developed by the authors and used in several pharmacokinetics studies. During the analysis of plasma and urine samples collected in those studies, an additional peak eluting just after topotecan was observed. Approximately 100 ng of this potential metabolite was isolated from human urine using a solid-phase extraction procedure and purification by HPLC. Analysis of the isolated material by HPLC showed it to be approximately 95% pure. Mass spectrometry data along with the HPLC retention data and fluorescence data (in comparison with synthetic reference standard) are consistent with the metabolite's being N-desmethyl topotecan. The maximal concentrations of metabolite detected in human plasma and urine were relatively low. When topotecan was given as a 30-min infusion at 1.0 mg/m2 daily for 5 days every 3 weeks, the maximal plasma metabolite concentration (lactone plus the ring-opened hydroxycarboxylate form) was about 0.7% (n = 4) of the maximal total topotecan concentration. The average amount of metabolite excreted in urine during the treatment was 1-4% (n = 20) of the delivered dose.