Continuous infusion carboplatin on a 21-day schedule: a phase I and pharmacokinetic study

Abstract

A phase I study with continuous infusion carboplatin for 21 days every 6 weeks using a venous access port and portable pump was performed over a dose range of 12 to 32 mg/m2/d, with increments of 2 mg/m2/d. Forty-four patients received 107 courses (median, two; range, one to nine). World Health Organization (WHO) grade III/IV leukopenia and thrombocytopenia occurred in one of seven patients at 30 mg/m2/d, and in two of six and four of six patients at 32 mg/m2/d. Cumulative platelet depression was found at dose levels of 28 mg/m2/d or more. Median glomerular filtration rate (GFR) and effective renal plasma flow, monitored by radioisotope clearances at doses greater than or equal to 20 mg/m2/d, decreased 8.2% (P less than .05) and 10.9% (P less than .01) after two courses. There was a relationship (r = .50, P less than .0002) between the percentage of platelet depression and GFR. No other toxicity was observed. Of the 17 patients who were evaluable, one complete response and four partial responses were observed. In addition, six patients had stable disease. Pharmacokinetic analysis of total and ultrafiltrable platinum (UFPt) was performed by atomic absorption spectrophotometry. Steady-state plasma levels for UFPt were reached after 8 hours. These levels could be detected from the 20 mg/m2/d dose. During steady state, carboplatin dose and UFPt plasma levels were not correlated, but steady-state UFPt and GFR (r = -.27, P less than .05) were. Twenty-four percent of total platinum (Pt) was present as UFPt during steady state (x = 160 +/- 10 micrograms/L). Total body clearance of UFPt exceeded GFR 2.2 times. Mean area under the curve (AUC) for UFPt during continuous infusion was 4,921.8 +/- 301.72 mg.min/L. For total Pt, steady-state plasma levels were not reached; total Pt plasma levels increased between day 7 and day 21 (P less than .0001). There was a significant relation between total Pt serum levels day 7, 14, and 21 and the drug dose administered. Immunohistochemical analysis of DNA-bound Pt in leukocytes showed a linear increase from day 7 to day 14 to day 21 (r = .97) between DNA-bound Pt and duration of infusion in individual patients. The maximum-tolerable dose of carboplatin is 30 mg/m2/d for 21 days (total dose 630 mg/m2) and is recommended for phase II studies.