Pharmacokinetic, metabolic, and pharmacodynamic profiles in a dose-escalating study of irinotecan and cisplatin

Purpose: To investigate the pharmacokinetics and pharmacodynamics of irinot ecan and cisplatin administered once every 3 weeks in a dose-escalating stu dy in patients with solid tumors. Patients and Methods: Fifty-two cancer patients were treated with irinoteca n administered as a 90-minute infusion a, doses ranging from 175 to 300 mg/ m(2) followed by cisplatin administered as a 3-hour intravenous infusion at doses ranging from 60 to 80 mg/m2, After reaching the maximum-tolerated do se, the sequence of drug administration was revised. For pharmacokinetic an alysis, serial plasma samples were obtained on days 1 through 3 of the firs t cycle. Forty-five patients were assessable for irinotecan pharmacokinetic s, and 46 were assessable for cisplatin pharmacokinetics. Results: Irinotecan and cisplatin demonstrated linear pharmacokinetics comp arable to that observed with single-agent administration, which suggests an absence of pharmacokinetic interaction. SN-38G constituted the major plasm a metabolite of irinotecan, whereas 7-ethyl-10-[4-N(1-piperidino)1-amino]-c arbonyloxycamptothecine (NPC) was only a minor metabolite in plasma, possib ly indicating a rapid conversion of NPC to SN-38. The terminal elimination phases of SN-38 and SN-38G were similar and relatively delayed when compare d with the elimination of irinotecan. Maximal DNA adduct formation did not significantly differ from that observed with single-agent administration. T he percentage decrease in WBC was significantly related to the areas under the plasma concentration-time curve (AUCs) of the lactone form of irinoteca n (P = .0245) and SN-38 (P = .0123). The severity of diarrhea was not signi ficantly related to the AUCs of irinotecan and SN-38, nor to the systemic g lucuronidation rate of SN-38. Conclusion: There was no apparent pharmacokinetic interaction between irino tecan and cisplatin in this study. Reversion of the administration sequence of the drugs did not seem to have any influence on the pharmacokinetics. T he incidence and severity of delayed-type diarrhea was not related to any o f the studied parameters. (C) 2000 by American Society of Clinical Oncology .