PHASE-I AND PHARMACOLOGICAL STUDIES OF TOPOTECAN IN PATIENTS WITH IMPAIRED HEPATIC-FUNCTION

Background: Topotecan, a topoisomerase I inhibitor that has demonstrat ed anticancer activity toward leukemias and solid tumors in clinical t rials, is eliminated via hepatic and renal routes. However, dosing gui delines for the administration of topotecan to patients with impaired hepatic function have not yet been established. Purpose: We compared t he maximum tolerated doses (MTDs), the toxic effects, and the pharmaco kinetics and pharmacodynamics of topotecan in patients who had refract ory, malignant, solid tumors and who either had or lacked hepatic inju ry. The potential role of three substrate markers of liver function (i ndocyanin green [ICG]-a marker of hepatic blood flow; lorazepam-a subs trate marker of hepatic glucuronidation; and antipyrine-a substrate ma rker for cytochrome P450 activity) in optimizing topotecan doses for p atients with liver injury was also evaluated. Methods: Twenty-one canc er patients, 14 of whom had hepatic injury due to metastatic disease, biliary obstruction, or cirrhosis, were treated with intravenously del ivered courses of topotecan consisting of 0.5, 1.0, or 1.5 mg/m(2) of drug per day for 5 days. Most patients received more than one course o f treatment, with new courses initiated at 3-week intervals. Patient r esponses (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 an tipyrine to determine the plasma pharmacokinetics of these compounds. The pharmacokinetics of topotecan (both the lactone and the carboxylat e forms) were determined by analysis of plasma and urine samples colle cted on the first day of the first course of drug treatment. Scatter p lots of area under the plasma concentration versus time curves in rela tion to percent decreases in either absolute neutrophil count or plate let count were used to explore the pharmacodynamics of topotecan. The Student's t test and the Mann-Whitney U test were used to compare phar macokinetic parameters between patients with and without abnormal hepa tic function. Correlations were assessed using the Spearman's rank cor relation coefficient (r(S)). Reported P values are based on two-tailed tests of significance. Results: Patients with hepatic injury tolerate d topotecan doses up to 1.5 mg/m(2), i.e., the MTD of this drug establ ished in previous studies. The nature and severity of treatment-induce d toxic effects and the pharmacokinetics of topotecan were similar in patients with and without liver injury. No differences were observed i n the urinary excretion of topotecan between the two patient groups. C learances of total topotecan and of its lactone species correlated onl y with clearance of ICG (r(S) = .64, P = .004; and r(S) = .68, P = .00 17, respectively). The pharmacodynamic effects of topotecan were not a ltered by liver dysfunction. Conclusions and Implications: Cancer pati ents with hepatic injury can be treated with topotecan at a starting d ose of 1.5 mg/m(2), given daily for 5 days and administered every 3 we eks. Topotecan dose modifications do not appear to be required for pat ients with hepatic dysfunction and normal renal function.