PHASE-I PHARMACOKINETIC STUDY OF TOPOTECAN BY 24-HOUR CONTINUOUS-INFUSION WEEKLY

Topotecan (SK&F 104864, hycamptamine, NSC 609699) is believed to exert its cytotoxic effects through inhibition of topoisomerase I, the acti vity of which recovers rapidly on removal of the drug in vitro. In viv o studies show that the activity of topotecan is schedule dependent, f avoring repeated doses. Early human studies showed that topotecan (the active lactone) had a short half-life in plasma. To prolong drug expo sure, we administered topotecan as a 24-h i.v. infusion and repeated i t weekly. We treated 32 patients with doses of 1.0-2.0 mg/m(2). Median performance status was 1, and all but four patients had received prio r chemotherapy. Dose-limiting neutropenia occurred at doses greater th an or equal to 1.75 mg/m(2); nadirs were observed after 1-3 doses. The recommended phase II dose is 1.5 mg/m(2)/ week One patient with metas tatic colon cancer had a partial response. Both plasma topotecan (lact one) and total topotecan (measured by converting the hydroxyacid form to the lactone by acidification of the sample) were measured by high-p erformance liquid chromatography in 21 patients. During infusion, mean topotecan plasma steady-state concentrations ranged from 4.7-11.4 nM. Plasma elimination was best fit to a one-compartment model with a mea n t(1/2) of 3.5 h. The mean total body clearance was 388 mI/min/m(2). Concentrations of the inactive form approximated those of the lactone throughout. No evidence for dose-dependent pharmacokinetics was observ ed in this dose range. Pharmacodynamic analysis, using the sigmoid E(m ax) model, revealed that the pharmacokinetic parameters of both lacton e and total drug were positively correlated with bone marrow toxicity. Total drug steady-state plasma concentration provided a goad estimate of neutropenia, suggesting a simple, easily monitored, pharmacokineti c parameter for adaptive dosing using this schedule. Phase II evaluati on of this weekly schedule is indicated in solid tumors.