ABSTRACT
The aims of this study were to determine the maximum tolerated dose (MTD), toxicity and pharmacokinetics of oral temozolomide administered over 42 d in children with recurrent/refractory brain tumours. Cohorts of 3-6 patients were treated for 42 d, followed by a 7-d rest period for a maximum of 6 cycles. Patients were stratified as heavily pre-treated (HPT) and non-heavily pre-treated (NHPT). Starting doses were 50 mg/m2 (HPT) or 75 mg/m2 (NHPT). Out of 28 patients enrolled, 20 were evaluable for toxicity and 19 for pharmacokinetics. Three patients in the NHPT group developed grade 3/4 haematological toxicity, 2 experienced dose-limiting toxicity (thrombocytopenia) at 100 mg/m2, and 9/20 developed grade 3 lymphopenia. MTD in both strata was 85 mg/m2. Responses were observed in 4 patients: 2 complete responses (CR) in medulloblastoma and supratentorial primitive neuroectodermal tumours (PNET), and 2 partial responses (PR) in high-grade glioma, respectively. Overall cumulative exposure was at least 1.5 times higher than in the 5-d administration schedule. In conclusion, the recommended dose of temozolomide is 85 mg/m2 x 42 d. Dose-limiting toxicities are thrombocytopenia and lymphopenia. The observed response rate warrants phase II studies.
Subject(s)
Antineoplastic Agents, Alkylating/administration & dosage , Brain Neoplasms/drug therapy , Dacarbazine/analogs & derivatives , Neoplasm Recurrence, Local/drug therapy , Administration, Oral , Antineoplastic Agents, Alkylating/adverse effects , Antineoplastic Agents, Alkylating/pharmacokinetics , Brain Neoplasms/pathology , Child , Dacarbazine/administration & dosage , Dacarbazine/adverse effects , Dacarbazine/pharmacokinetics , Dose-Response Relationship, Drug , Drug Administration Schedule , Feasibility Studies , Female , Humans , Male , Neoplasm Recurrence, Local/pathology , TemozolomideABSTRACT
High-performance liquid chromatography separation of reduced and oxidized glutathione (GSH and GSSG) in biologic samples using electrochemical detection offers the convenience of both simultaneous quantitation and simple sample preparation. Rapid acidification is required to prevent GSH autooxidation, GSH and GSSG degradation, and precipitate proteins that interfere with analysis. Currently, little consistency exists in the literature regarding acid selection or the feasibility of sample storage before analysis. The purpose of this work was to examine the effects of perchloric (PCA), trichloroacetic (TCA), metaphosphoric (MPA), and 5-sulfosalicylic (SSA) acids on the short-term stability of GSH and GSSG measurements in whole blood. Samples were collected from adult volunteers and treated with multiple concentrations of each acid. The samples were analyzed immediately and aliquots were stored at -80 degrees C for up to 28 days. The suitability of each acid was assessed by percentage change of GSH and GSSG from baseline, efficiency of protein removal, and alteration of chromatogram characteristics. In general, increasing the acid concentration improved sample stability. Nevertheless, SSA did not achieve acceptable sample stability at any concentration tested. MPA was found to leave substantial amounts of protein in the samples, and TCA may interfere with the peaks of interest. Based on these results, a final concentration of 15% PCA is suggested for analysis of glutathione in whole blood. Although immediate sample preparation is preferred, 15% PCA can maintain sample integrity for 4 weeks after storage at -80 degrees C.
Subject(s)
Glutathione Disulfide/blood , Glutathione/blood , Adult , Benzenesulfonates , Blood Proteins/metabolism , Chromatography, High Pressure Liquid , Drug Stability , Humans , Oxidation-Reduction , Perchlorates/pharmacokinetics , Phosphorous Acids/pharmacokinetics , Salicylates/pharmacokinetics , Trichloroacetic Acid/pharmacokineticsABSTRACT
BACKGROUND: Amifostine protects normal tissues against chemotherapy and radiation-induced toxicity without loss of antitumor effects. Evidence suggests that multiple daily doses of amifostine may improve its cytoprotective effects. The purpose of this study was to assess the dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) of twice-daily doses of amifostine with ifosfamide, carboplatin, and etoposide (ICE) chemotherapy for children with refractory malignancies and to determine the pharmacokinetic properties of amifostine, WR-1065, and the disulfide metabolites of amifostine. METHODS: Patients with refractory malignancies were treated with amifostine 15 minutes before and 2 hours after chemotherapy with ifosfamide (3 g/m(2) per dose on Days 1 and 2) and carboplatin (635 mg/m(2) on Day 3). Etoposide was administered on Days 1 and 2 (150 mg/m(2)). The starting dose of amifostine was 740 mg/m(2). Pharmacokinetic studies were performed after the first dose of amifostine. RESULTS: Twelve patients received 23 courses of ICE and amifostine. Dose-limiting toxicities for amifostine at 740 mg/m(2) were somnolence and anxiety. The other Grade 3 and 4 toxicities included asymptomatic, reversible hypocalcemia, vomiting, and reversible hypotension. At a dose of 600 mg/m(2), amifostine was well tolerated. Hypocalcemia, due to rapid, transient suppression of parathyroid hormone production, required close monitoring and aggressive intravenous calcium supplementation. Pharmacokinetic studies revealed high interpatient variability with rapid plasma clearance of amifostine and WR-1065. The median elimination half-life of amifostine (9.3 minutes) and WR-1065 (15 minutes) was much shorter than the disulfide metabolites (74.4 minutes). CONCLUSIONS: The recommended pediatric dose of amifostine for a twice-daily regimen is 600 mg/m(2) per dose (1200 mg/m(2)/day) with DLTs of anxiety and somnolence, lower than the previously recommended single dose of 1650 mg/m(2).
