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Topotecan is a novel semisynthetic derivative of the anticancer agent camptothecin and inhibits the intranuclear enzyme topoisomerase I. The lactone structure of topotecan, which is in equilibrium with the inactive ring-opened hydroxy acid, is essential for this activity. The open form predominates at physiological pH. We performed a pharmacokinetic study as part of a phase I study in patients with various types of solid tumors, where topotecan was administered in a 30-min infusion daily on 5 consecutive days every 3 weeks. The plasma kinetics of topotecan could be described best using an open two-compartment model with t1/2(alpha) and t1/2(beta) of 8.1 (range 0.3 to 40.7) min and 132 (range 49 to 286) min, respectively. The plasma concentration-time profiles of the metabolite, however, could be described using a one-compartment model with t1/2(formation) of 29.0 (range 5.6-99.5) min and t1/2 (elimination of 123.2 (range 32-265) min, respectively. The lactone was the predominate form during the first hour from the start of infusion, but was rapidly converted into its ring-opened structure. The elimination rate of topotecan was independent of the dose. There were linear relationships between the dose (mg m-2 day-1), the area under the plasma concentration versus time curve (AUC) of topotecan and its metabolite, the total AUC, peak plasma lactone concentrations, and the time period that the topotecan concentrations remained above 10 nM. Different models were used to correlate pharmacokinetic and pharmacodynamic parameters. The percentage decrease in absolute neutrophil count (ANC) was related to these parameters and plots were well fitted by linear and sigmoidal Emax models. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the pharmacokinetics and pharmacodynamics of irinotecan and cisplatin administered once every 3 weeks in a dose-escalating study in patients with solid tumors., Patients and Methods: Fifty-two cancer patients were treated with irinotecan administered as a 90-minute infusion at doses ranging from 175 to 300 mg/m(2) followed by cisplatin administered as a 3-hour intravenous infusion at doses ranging from 60 to 80 mg/m(2). After reaching the maximum-tolerated dose, the sequence of drug administration was revised. For pharmacokinetic analysis, serial plasma samples were obtained on days 1 through 3 of the first cycle. Forty-five patients were assessable for irinotecan pharmacokinetics, and 46 were assessable for cisplatin pharmacokinetics., Results: Irinotecan and cisplatin demonstrated linear pharmacokinetics comparable to that observed with single-agent administration, which suggests an absence of pharmacokinetic interaction. SN-38G constituted the major plasma metabolite of irinotecan, whereas 7-ethyl-10-[4-N-(1-piperidino)1-amino]-carbonyloxycamptothecine (NPC) was only a minor metabolite in plasma, possibly indicating a rapid conversion of NPC to SN-38. The terminal elimination phases of SN-38 and SN-38G were similar and relatively delayed when compared with the elimination of irinotecan. Maximal DNA adduct formation did not significantly differ from that observed with single-agent administration. The percentage decrease in WBC was significantly related to the areas under the plasma concentration-time curve (AUCs) of the lactone form of irinotecan (P =.0245) and SN-38 (P =. 0123). The severity of diarrhea was not significantly related to the AUCs of irinotecan and SN-38, nor to the systemic glucuronidation rate of SN-38., Conclusion: There was no apparent pharmacokinetic interaction between irinotecan and cisplatin in this study. Reversion of the administration sequence of the drugs did not seem to have any influence on the pharmacokinetics. The incidence and severity of delayed-type diarrhea was not related to any of the studied parameters.

Purpose: To assess the feasibility, pharmacokinetic interaction, and possible sequence-dependent effects of the irinotecan/cisplatin combination given every 3 weeks, and to assess the influence of additional granulocyte colony-stimulating factor (G-CSF) on the hematologic toxicity., Patients and Methods: Patients who had received no more than one prior combination chemotherapy regimen or two single-agent regimens were entered. Treatment consisted of a 90-minute irinotecan infusion followed by a 3-hour cisplatin infusion on day 1, with cycles repeated once every 3 weeks. After the maximum-tolerated dose was determined, the sequence of administration was reversed. In a separate cohort of six patients, we assessed the effect of G-CSF on the experienced hematologic toxicity and dose-intensity. Irinotecan doses ranged from 175 to 300 mg/m(2) and cisplatin doses ranged from 60 to 80 mg/m(2)., Results: Fifty-two patients entered the study; one was not eligible, and two were not assessable for response. Twenty-five patients were pretreated, and 26 were not. Fifty-one patients received a total of 223 courses. The dose-limiting toxicity was a combination of neutropenic fever, diarrhea, and fatigue at a dose level combining irinotecan 300 mg/m(2) with cisplatin 80 mg/m(2). Neutropenia was common (grades 3 to 4, 68%). Irinotecan pharmacokinetics were linear over the dose range studied. No sequence-dependent side effects were observed. Tumor responses included three complete responses and eight partial responses., Conclusion: For phase II studies, we recommend irinotecan 260 mg/m(2) combined with cisplatin 80 mg/m(2) once every 3 weeks for chemotherapy-naive patients in good physical condition, and irinotecan 200 mg/m(2) combined with cisplatin 80 mg/m(2) for other patients.

A phase I study was conducted to characterize the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and pharmacokinetics of a single dose followed by three times weekly s.c. injections of recombinant human interleukin 12 (rHuIL-12). The study encompassed 28 patients with advanced renal cell carcinoma. rHuIL-12 was administered on day 1, followed by an observation period of 7 days. Starting on day 8, repeated s.c. injections were administered 3 times a week for 2 weeks. The MTD of the initial injection was evaluated at dose levels of 0.1, 0.5, and 1.0 microg/kg. DLT was observed at 1.0 microg/kg and consisted of fever, perivasculitis of the skin, and leukopenia. The MTD of the subsequent repeated injections after 1 week of rest was studied at dose levels 0.5, 1.0, and 1.25 microg/kg. DLT at 1.25 microg/kg comprised deterioration of performance status, fever, vomiting, mental depression, and leukopenia. Other notable toxicities were oral mucositis and elevation of hepatic enzymes. Fever, leukopenia, and elevation of hepatic enzymes were more severe after the initial injection than after repeated injections at the same dose level. At dose level 0.5 microg/kg, the mean area under the plasma concentration-time curve decreased from 7.4 ng/h/ml after the first injection to 3.3 ng x h/ml (P = 0.034) after repeated administrations, and at dose level 1.0 microg/kg, it ranged from 31.8 ng/h/ml to 6.0 ng x h/ml (P = 0.041). One patient had a partial response and seven had stable disease. The MTD of a single s.c. injection of rHuIL-12 was 0.5 microg/kg, and the MTD of three subsequent administrations per week was 1.0 microg/kg. In comparison with a single administration, the three times weekly administrations at the same dose level was accompanied with a milder pattern of side effects and a reduction of the area under the plasma concentration-time curve.

BMS-181174, a new mitomycin C (MMC) analog, showed more activity than the parent compound in tumor xenografts. In a phase I study with a 5-30 min slow bolus administration, hematologic and vascular toxicity were observed as major side effects. A prolonged infusion was suggested to circumvent the vascular toxicity. In this phase I study BMS-181174 was administered as a 6 h infusion every 4 weeks; the doses studied were 3.2, 6.4, 11.5, 19.0, 32.0, 50.0, 75.0 and 100 mg/m2. Twenty-eight patients were enrolled in the study, the majority with colorectal cancer. Hematologic side effects consisted of thrombocytopenia, and mild leuko- and granulocytopenia. The most distressing non-hematologic side effect was vascular toxicity consisting of phlebosclerosis and phlebitis, becoming dose limiting at 100 mg/m2. One patient developed a hemolytic uremic syndrome at a cumulative dose of 350 mg/m2. Pharmacokinetic data are available for 24 patients. The AUC ranged from 3.35 to 41.49 (microg x h/ml) and was highly correlated with the dose administered (r = 0.83). The kinetics appeared to be linear. One patient with metastatic colon cancer had a partial response of liver metastases. BMS-181174 is a MMC analog with a toxicity profile comparable to that of the parent compound. As doses above 50 mg/m2 are complicated by vascular toxicity precluding multiple administrations, further exploration of BMS-181174 will not be performed.