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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/[m.sup.2] 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 coeffcient ([r.sub.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/[m.sup.2], 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.sub.s] = .64, P = .004; and [r.sub.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/[m.sub.2], 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.

Histamine-2 receptor antagonists (H2RAs) are principal components of the premedication regimen used to prevent major hypersensitivity reactions in patients receiving paclitaxel. Several different H2RAs, including cimetidine, ranitidine and famotidine, have been used in clinical trials of paclitaxel, as well as by clinicians in different geographic regions and hospitals primarily because of differences in the availability of the various H2RAs. However, H2RAs have highly variable cytochrome P450-modulating capabilities, and the P450 system appears to play a major role in paclitaxel metabolism and disposition. Therefore, the use of different H2RAs may result in different pharmacologic, toxicologic and antitumor profiles due to differential effects on paclitaxel metabolism. This study evaluated whether cimetidine and famotidine, which possess disparate P450-modulating capabilities, differentially affect paclitaxel clearance rates and the agent's principal toxicity, neutropenia. Women with advanced, platinum-refractory ovarian carcinoma received two courses of treatment with 135 mg/m2 paclitaxel over 24 h while participating in the National Cancer Institute's Treatment Referral Center Protocol. A crossover design was employed in which consecutive patients received either 300 mg cimetidine i.v. or 20 mg famotidine i.v. before their first course of paclitaxel and the alternate H2RA before their second course. In order to evaluate the differential effects of cimetidine and famotidine on pertinent pharmacologic and toxicologic parameters in the same individual, paclitaxel concentrations at steady-state (Css), paclitaxel clearance rates, and absolute neutrophil counts (ANCs) were obtained during both courses. Paclitaxel Css values were not significantly different in individual patients when either cimetidine or famotidine preceded paclitaxel (p=0.16). Mean paclitaxel clearance rates were 271 and 243 ml/min per m2 following cimetidine and famotidine, respectively. These clearance rates were not significantly different in paired analysis (p=0.30). The likelihood of subsequently requiring granulocyte-colony stimulating factor (G-CSF) for severe neutropenia during course 1 did not differ significantly between the two H2RAs (p=0.9). Among patients who did not require G-CSF, mean percentage decreases in ANC were 87.7% and 84.2% after paclitaxel cycles preceded by cimetidine and famotidine, respectively. These measures of neutropenia did not differ significantly in paired analysis (p=0.13). These results show that the H2RAs cimetidine and famotidine do not differentially affect the pharmacologic and toxicity profiles of paclitaxel when used in the premedication regimen to prevent major hypersensitivity reactions, and may be interchanged.