Phase I and pharmacologic studies of topotecan in patients with impaired hepatic function

Background: Topotecan, a topoisomerase I inhibitor that has demonstrated anticancer activity toward leukemias and solid tumors in clinical trials, is eliminated via hepatic and renal routes. However, dosing guidelines for the administration of topotecan to patients with impaired hepatic function have not yet been established. Purpose: We compared the maximum tolerated doses (MTDs), the toxic effects, and the pharmacokinetics and pharmacodynamics of topotecan in patients who had refractory, malignant, solid tumors and who either had or lacked hepatic injury. The potential role of three substrate markers of liver function (indocyanin green [ICG]-a marker of hepatic blood flow; lorazepam-a substrate marker of hepatic glucuronidation; and antipyrine-a substrate marker for cytochrome P450 activity) in optimizing topotecan doses for patients with liver injury was also evaluated. Methods: Twenty-one cancer patients, 14 of whom had hepatic injury due to metastatic disease, biliary obstruction, or cirrhosis, were treated with intravenously delivered courses of topotecan consisting of 0.5, 1.0, or 1.5 mg/m² of drug per day for 5 days. Most patients received more than one course of treatment, with new courses initiated at 3-week intervals. Patient responses (evaluated by tumor measurements) and treatment-induced toxic effects were assessed. Prior to the initiation of topotecan treatment, patients were given intravenous injections of ICG, lorazepam, and antipyrine to determine the plasma pharmacokinetics of these compounds. The pharmacokinetics of topotecan (both the lactone and the carboxylate forms) were determined by analysis of plasma and urine samples collected on the first day of the first course of drug treatment. Scatter plots of area under the plasma concentration versus time curves in relation to percent decreases in either absolute neutrophil count or platelet count were used to explore the pharmacodynamics of topotecan. The Student's t test and the Mann-Whitney U test were used to compare pharmacokinetic parameters between patients with and without abnormal hepatic function. Correlations were assessed using the Spearman's rank correlation coefficient (r(s)). Reported P values are based on two-tailed tests of significance. Results: Patients with hepatic injury tolerated topotecan doses up to 1.5 mg/m², i.e., the MTD of this drug established in previous studies. The nature and severity of treatment-induced toxic effects and the pharmacokinetics of topotecan were similar in patients with and without liver injury. No differences were observed in the urinary excretion of topotecan between the two patient groups. Clearances of total topotecan and of its lactone species correlated only with clearance of ICG (r(s) = .64, P = .004; and r(s) = .68, P = .0017, respectively). The pharmacodynamic effects of topotecan were not altered by liver dysfunction. Conclusions and Implications: Cancer patients with hepatic injury can be treated with topotecan at a starting dose of 1.5 mg/m², given daily for 5 days and administered every 3 weeks. Topotecan dose modifications do not appear to be required for patients with hepatic dysfunction and normal renal function.