Cisplatin disposition in children and adolescents with cancer

Abstract

The disposition of cisplatin was evaluated in 28 children and adolescents with cancer, as part of a phase II clinical trial. Patients received either 30 mg/m2 (11) or 90 mg/m2 (17) of cisplatin as a 6-h IV infusion. Serum samples and divided urine collections were obtained over 48 h following completion of the cisplatin infusion, and were assayed in duplicate for total platinum by atomic absorption spectrophotometry. Serum samples obtained up to 4 h after three cisplatin infusions were assayed for parent (free) cisplatin following ultrafiltration. The mean (+/- SE) elimination half-life of free cisplatin in serum was 1.3 (+/- 0.4) h. Serial serum concentrations of total platinum following 90 mg/m2 dosages were adequately described by a biexponential equation. The mean (+/- SE) serum T 1/2 alpha of total platinum was 0.42 (+/- 0.10) h and the mean (+/- SE) T 1/2 beta was 44.43 (+/- 8.24) h. The intercompartment distribution rate constants of a two-compartment kinetic model indicate extensive tissue accumulation of total platinum, with a rate of transport into tissue compartments (K12) that is about six times the rate of transport out of tissues (K21). The mean (+/- SE) renal clearance of total platinum from 0-3 h was 37.36 (+/- 11.96) ml/min/m2 and 35.8 (+/- 13.6) ml/min/m2 for the 30 mg/m2 and 90 mg/m2 groups, respectively. This value decreased to 3.25 (+/- 0.94) and 2.16 (+/- 0.4) ml/min/m2 for the two groups by the 6-12 h interval, and remained between 1 and 3 ml/min/m2 for the duration of the observation period. The ratio of total platinum clearance to creatinine clearance decreased significantly (P less than 0.05) beginning 3 h post-infusion. The change in renal clearance of total platinum is apparently a function of two independent first-order processes for renal clearance of parent drug and cisplatin metabolites.