Abstract
Pharmacokinetics of the cisplatin analogue carboplatin were studied in patients with disseminated ovarian and testicular cancer. Carboplatin 750 mg m-2 divided over three consecutive days was given as part of an ablative combination regimen followed by autologous bone marrow transplantation. Platinum (Pt) in plasma, plasma ultrafiltrate and urine was determined up to 96 h after the last drug dose by atomic absorption spectrometry. Carboplatin was measured by high performance liquid chromatography. The curves of ultrafiltrated Pt and carboplatin decayed in a bio-exponential way with t1/2 alpha of respectively 65 and 70 min and t1/2 beta of respectively 378 and 1014 min. The volumes of distribution (Vdss) were 18 and 25 l m-2, respectively, and total body clearances (ClTB) 79 and 65 ml min-1 m-2. Both curves overlapped when corrected for the Pt content of carboplatin. A diversion with the three-exponential curve of total Pt occurred between 3 and 6 h. After 10 h approximately 30% of the plasma Pt was protein bound. Total Pt had a larger Vdss (117 l m-2) and a lower total body clearance (14 ml min-1 m-2) than free Pt and carboplatin. Fifty-three per cent of the i.v. administered carboplatin was excreted in the urine in the first 6 h. Plasma ultrafiltrated Pt and carboplatin decreased to undetectable levels within 48 h, but total Pt was detectable until 96 h after the last carboplatin dose. However, this Pt is already bound to protein and unlikely to be cytotoxic to reinfused haemopoietic stem cells, so bone marrow reinfusion can be safely performed at 48 h after repeated dosing of carboplatin on three consecutive days.
Highlights
Nephrotoxicity has been described (Curt et al, 1983; Rozencweig et al, 1983; Mulder et al, 1988), it is not a major side-effect of this drug and its occurrence is in part, though not entirely, dose-related (Gore et al, 1987). Other toxicities, such as nausea and vomiting, are less severe compared to cisplatinum, while neurotoxicity is absent at conventional doses and grade 1 neuropathy is sporadically seen in patients receiving 1,200 mg m-2 or more (Calvert et al, 1982; Rose & Schurig, 1985; Ozols et al, 1985; Canetta et al, 1985; Gore et al, 1987)
The five patients who were entered in this study with highdose chemotherapy and autologous bone marrow reinfusion had end-stage ovarian cancer or relapsed testicular cancer
Carboplatin 250 mg -2 was dissolved in 500 ml of dextrosesaline (2.5% ± 0.45%) and given intravenously over 30 min every 24 h on three consecutive days
Summary
Nephrotoxicity has been described (Curt et al, 1983; Rozencweig et al, 1983; Mulder et al, 1988), it is not a major side-effect of this drug and its occurrence is in part, though not entirely, dose-related (Gore et al, 1987). Other toxicities, such as nausea and vomiting, are less severe compared to cisplatinum, while neurotoxicity is absent at conventional doses and grade 1 neuropathy is sporadically seen in patients receiving 1,200 mg m-2 or more (Calvert et al, 1982; Rose & Schurig, 1985; Ozols et al, 1985; Canetta et al, 1985; Gore et al, 1987)
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