Phase I/pharmacokinetic study of topotecan by 24-hour continuous infusion weekly

Abstract

Topotecan (SK&F 104864, hycamptamine, NSC 609699) is believed to exert its cytotoxic effects through inhibition of topoisomerase I, the activity of which recovers rapidly on removal of the drug in vitro. In vivo studies show that the activity of topotecan is schedule dependent, favoring repeated doses. Early human studies showed that topotecan (the active lactone) had a short half-life in plasma. To prolong drug exposure, we administered topotecan as a 24-h i.v. infusion and repeated it weekly. We treated 32 patients with doses of 1.0-2.0 mg/m2. Median performance status was 1, and all but four patients had received prior chemotherapy. Dose-limiting neutropenia occurred at doses > or = 1.75 mg/m2; nadirs were observed after 1-3 doses. The recommended phase II dose is 1.5 mg/m2/week. One patient with metastatic colon cancer had a partial response. Both plasma topotecan (lactone) and total topotecan (measured by converting the hydroxyacid form to the lactone by acidification of the sample) were measured by high-performance 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 mean t1/2 of 3.5 h. The mean total body clearance was 388 ml/min/m2. Concentrations of the inactive form approximated those of the lactone throughout. No evidence for dose-dependent pharmacokinetics was observed in this dose range. Pharmacodynamic analysis, using the sigmoid Emax model, revealed that the pharmacokinetic parameters of both lactone and total drug were positively correlated with bone marrow toxicity. Total drug steady-state plasma concentration provided a good estimate of neutropenia, suggesting a simple, easily monitored, pharmacokinetic parameter for adaptive dosing using this schedule. Phase II evaluation of this weekly schedule is indicated in solid tumors.