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Drug-Administration Sequence Does Not Change Pharmacodynamics and Kinetics of Irinotecan and Cisplatin

Department of Medical Oncology, Rotterdam Cancer Institute (Daniel den Hoed Kliniek) and University Hospital Rotterdam, 3075 EA Rotterdam, the Netherlands [M. J. A. d. J., J. V., A. S. T. P., M. E. L. v. d. B., G. S., M. M. d. B-D., P. d. B., E. B., A. S.], and Rhône-Poulenc Rorer, 92165 Antony Cedex, France [L. V.]

In this study, 11 patients with solid tumors were randomized to receive irinotecan (CPT-11; 200 mg/m²) as a 90-min i.v. infusion, immediately followed by cisplatin (CDDP; 80 mg/m²) as a 3-h i.v. infusion in the first course and the reversed sequence in the second course or vice versa. No significant differences in any toxicity were observed between the treatment schedules (decrease in absolute neutrophil count, 74.7 ± 18.3 versus 80.3 ± 18.0%; P = 0.41). CPT-11 lactone clearance was similar to single agent data and not significantly different between study courses (60.4 ± 17.1 versus 65.5 ± 16.3 liter/h/m²; P = 0.66). The kinetic profiles of the major CPT-11 metabolites SN-38, SN-38 glucuronide, 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino]carbonyloxycamptothecine (APC), and 7-ethyl-10-[4-N-(1-piperidino)-1-amino]carbonyloxycamptothecine (NPC) were also sequence independent (P 0.20). In addition, CPT-11 had no influence on the clearance of nonprotein-bound CDDP (40.8 ± 16.7 versus 50.3 ± 18.6 liter/h/m²; P = 0.08) and the platinum DNA-adduct formation in peripheral leukocytes in either sequence (1.94 ± 2.20 versus 2.42 ± 1.62 pg Pt/µg DNA; P = 0.41). These data indicate that the toxicity of the combination CPT-11 and CDDP is schedule independent and that there is no mutual pharmacokinetic interaction.

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