A pharmacokinetic-pharmacodynamic study on carboplatin administered in prolonged continuous infusion regimens with synchronous radiotherapy

Abstract

A clinical and pharmacokinetic study was conducted on an outpatient basis in which carboplatin was administered by continuous infusion (20, 25, or 30 mg/d X 5 days X 4 weeks) with synchronous radio therapy. Responses were obtained in 8 of 15 patients, and dose-limiting toxicity was not reached. Leukope nia (grade 1 or 2) occurred in 8 patients, nausea (grade 1 or 2) in 2 patients, and no other toxicity was evident. AUC (area under plasma concentration X time curve) and elimination half-life (1.68 to 2.97 hours) data were similar to values obtained for the rapid intravenous (IV) infusion of carboplatin at an equivalent dose in previous studies. Values of volume of distribution at steady-state (Vdss) were higher following continuous infusion administration as com pared with rapid IV infusion. This was consistent with results from other studies and may possibly be ex plained by altered drug distribution and disposition following continuous infusion therapy. Data were fitted to a mono-exponential elimination curve that was also in agreement with previous reports on carboplatin pharmacokinetics. Relationships between pharmacokinetic variables and pharmacodynamic variables (haematological toxicity) were investigated in order to explore the possibility of developing pharmacokinetically guided dosage schemes for car boplatin given by continuous infusion in a combined modality treatment. A linear correlation (r = 0.71) was evident between the percentage decrease in platelets (at the nadir 4 weeks after the start of infusion) and AUC X normalised radiation field area. Wtih further studies, it is possible that a formula could be derived from this relationship for dose individual isation in patients receiving carboplatin by continu ous infusion with synchronous radiotherapy.