Drug-administration sequence does not change pharmacodynamics and kineticsof irinotecan and cisplatin

In this study, 11 patients with solid tumors were randomized to receive iri notecan (CPT-11; 200 mg/m(2)) as a 90-min i.v. infusion, immediately follow ed by cisplatin (CDDP; 80 mg/m(2)) as a 3-h i.v. infusion in the first cour se and the reversed sequence in the second course or vice versa. No signifi cant differences in any toxicity were observed between the treatment schedu les (decrease in absolute neutrophil count, 74.7 +/- 18.3 versus 80.3 +/- 1 8.0%; 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/m(2); P = 0.66), The kinetic profiles of the major C PT-11 metabolites SN-38, SN-38 glucuronide, 7-ethyl-10-[4-N-(5-aminopentano ic acid)-1-piperidino]carbonyloxycamptothecine (APC), and 7-ethyl-10-[4-N-( 1-piperidino)-1-amino]carbonyloxycamptothecine (NPC) were also sequence ind ependent (P greater than or equal to 0.20), In addition, CPT-11 had no infl uence on the clearance of nonprotein-bound CDDP (40.8 +/- 16.7 versus 50.3 +/- 18.6 liter/h/m(2): P = 0.08) and the platinum DNA-adduct formation in p eripheral leukocytes in either sequence (1.94 +/- 2.20 versus 2.42 +/- 1.62 pg Pt/mu g DNA; P = 0.41). These data indicate that the toxicity of the co mbination CPT-11 and CDDP is schedule independent and that there is no mutu al pharmacokinetic interaction.