A model for ultrafilterable plasma platinum disposition in patients treated with cisplatin

Abstract

A model incorporating recent information regarding the specificity of a high-performance liquid chromatographic assay for "active" platinum in plasma ultrafiltrate, and the concept of mobile and fixed metabolites, was developed for cancer patients treated with cisplatin. Model parameters were determined using plasma and urinary platinum data obtained in 20 patients. It was assumed in the model that parent drug accounted for essentially all the platinum measured in plasma ultrafiltrate in the 2 h period immediately post infusion. At times greater than 4 h post infusion, platinum concentrations in plasma ultrafiltrate were assumed to be due entirely to reactive, mobile metabolites with possible cytotoxicity. The model accurately simulated platinum concentrations in plasma ultrafiltrate over a 24-h period following a 2-h infusion of 80 mg/m2 of cisplatin to seven patients, 100 mg/m2 to ten patients and 120 mg/m2 to three patients.

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“…dose of cisplatin resulted in plasma total cisplatin AUC of 3228 mg*min/ml (10,758 mmol*min/ml), and another showed that an 18-mg/m 2 (6-mg/kg) dose produced an AUC of 134 mg*min/ml free cisplatin (Kubota et al, 1993;Lopez-Flores et al, 2005). A clinically relevant level of free cisplatin in plasma of mice is considered to be 81-519 mg*min/ml (Reece et al, 1987;van Hennik et al, 1987). Taking into account that the half-life is twice as long in mice compared with humans, and the LD 10 in nude mice was found to be 3.5 mg/kg weekly, we chose the dose of 3 mg/kg every 14 days (Reece et al, 1987;Taetle et al, 1987;van Hennik et al, 1987).…”

“…A clinically relevant level of free cisplatin in plasma of mice is considered to be 81-519 mg*min/ml (Reece et al, 1987;van Hennik et al, 1987). Taking into account that the half-life is twice as long in mice compared with humans, and the LD 10 in nude mice was found to be 3.5 mg/kg weekly, we chose the dose of 3 mg/kg every 14 days (Reece et al, 1987;Taetle et al, 1987;van Hennik et al, 1987).…”