A phase I and pharmacokinetics study of prolonged ambulatory-infusion carboplatin |
| |
Authors: | Ian N Olver Lorraine K Webster Michael J Millward Kerrie H Stokes James F Bishop |
| |
Institution: | (1) Division of Haematology and Medical Oncology, Peter MacCallum Cancer Institute, St. Andrews Place, 3002 East Melbourne, Victoria, Australia;(2) Royal Adelaide Hospital Cancer Service, North Terrace, 5000 Adelaide, South Australia, Australia |
| |
Abstract: | A total of 18 patients received 6-week ambulatory infusions of carboplatin in groups at dose levels of 14, 28, 35 and 42 mg/m2 per day. The dose-limiting toxicity was myelosuppression. At 42 mg/m2, three of four patients had WHO grade 4 and one of four had grade 3 neutropenia, whereas two patients had grade 3 thrombocytopenia. At 35 mg/m2, two of five patients had grade 3 neutropenia, whereas one had grade 4 and two had grade 3 thrombocytopenia. Non-hematological toxicities were predominantly gastrointestinal, with 3 of 18 patients experiencing grade 3 emesis. Total and ultrafiltrable platinum (UFPt) were assayed by flameless atomic absorption spectrometry in weekly and post-infusion plasma and urine samples. In plasma, levels of total platinum increased throughout the infusion, and the protein binding slowly increased from 60% platinum bound at week 1 to 90% bound by week 4. Although the UFPt level reached a steady state within 1 week, the concentration did not increase with the dose level, remaining at a mean value of 0.58±0.24 M. Renal excretion of platinum accounted for 70±12% of the dose at steady state. There was a high inter-patient variability in both total body clearance of UFPt (range, 83–603 ml/min) and renal clearance (range, 67–390 ml/min). A terminal elemination half-life of 13–27 h was noted for post-infusion UFPt. Neutropenia was linearly related to the total daily carboplatin dose, but neither neutropenia nor thrombocytopenia could be related to steady-state UFPt or the UFPt area under the concentration-time curve (AUC). The recommended dose for phase II studies is 28 mg/m2 per day. |
| |
Keywords: | Phase I Pharmacokinetics Carboplatin Ambulatory infusion |
本文献已被 SpringerLink 等数据库收录! |
|