Cancer chemotherapy and pharmacology
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Cancer Chemother. Pharmacol. · Jan 1999
Clinical TrialPlasma pharmacokinetics of N-[2-(dimethylamino)ethyl]acridine-4-carboxamide in a phase I trial.
DACA [N-[2-(dimethylamino)ethyl]acridine-4-carboxamide] is an acridine derivative with high activity against solid tumours in mice and a dual mode of cytotoxic action involving topoisomerases I and II. The plasma pharmacokinetics of DACA were studied in 28 patients with solid tumours in a phase I trial. A single dose was given every 3 weeks, being escalated from a starting dose of 18 mg/m2 (as the dihydrochloride trihydrate salt) to a maximal dose, limited by severe pain in the infusion arm, of 1000 mg/m2. ⋯ At the maximum tolerated dose (MTD) of 750 mg/m2, the area under the drug concentration-time curve (AUC) was 46.2+/-4.4 microM h, exceeding that obtained in mice treated at the MTD (23.4 microM h). On the other hand, the corresponding free-drug AUC was 0.92+/-0.03 microM h, much lower than the corresponding value (3.5 microM h) determined for mice. These results suggest that free-drug rather than total drug concentrations are more appropriate for interspecies dose comparisons when significant differences exist in the free plasma fraction.
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Cancer Chemother. Pharmacol. · Jan 1999
Inhibition of paclitaxel elimination in the isolated perfused rat liver by Cremophor EL.
Cremophor can alter the pharmacokinetics of cytotoxic drugs, including doxorubicin and etoposide. In view of its presence in the formulation of paclitaxel, the aim of this study was to investigate the influence of Cremophor on the hepatobiliary elimination of paclitaxel. ⋯ Cremophor inhibits the hepatic elimination of paclitaxel in the isolated perfused rat liver, primarily by preventing the drug from reaching sites of metabolism and excretion. The presence of Cremophor in the paclitaxel formulation may therefore contribute to the nonlinear pharmacokinetics and pharmacodynamics of paclitaxel.
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Cancer Chemother. Pharmacol. · Jan 1998
Synergistic cytotoxicity of cisplatin and topotecan or SN-38 in a panel of eight solid-tumor cell lines in vitro.
The cytotoxicity of cisplatin alone and in combination with topotecan (TPT) or SN-38, two novel topoisomerase I (topo I) inhibitors, was determined in a panel of eight well-characterized human solid-tumor cell lines. Interactions between cisplatin and these topo I inhibitors were investigated using three different administration schedules: (1) simultaneous incubation (C + T and C + S), (2) cisplatin followed by TPT or SN-38 (C --> T and C --> S), and (3) TPT or SN-38 followed by cisplatin (T --> C and S --> C). Median-effect analysis revealed synergistic cytotoxicity in seven of the eight cell lines used. ⋯ After exposure to TPT a different pattern was observed that was cell-type-specific and dependent upon the TPT concentration. Although up to 4-fold differences in topo I activity were observed in this panel of cell lines, these differences did not appear to be related to the synergy observed between cisplatin and TPT or SN-38. The observed synergy may at least partly be explained by the increased retention of cisplatin-DNA interstrand cross-links in the presence of topo I inhibitors.
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Cancer Chemother. Pharmacol. · Jan 1998
Multicenter Study Clinical TrialA clinical pharmacokinetics study of carzelesin given by short-term intravenous infusion in a phase I study.
We investigated the pharmacokinetic behavior of carzelesin in 31 patients receiving this drug by 10-min intravenous infusion in a Phase I clinical trial, which was conducted at institutions in Nijmegen (institution 1) and Brussels (institution 2). The dose steps were 24, 48, 96, 130, 150, 170, 210, 250, and 300 microg/m2. Carzelesin is a cyclopropylpyrroloindole prodrug that requires metabolic activation via U-76,073 to U-76,074. ⋯ The results recorded for patients in institution 1 indicated that the AUC increased proportionately with increasing doses. There was a good correlation between the maximal plasma concentration and the AUC, enabling future monitoring of drug exposure from one timed blood sample. Urinary excretion of carzelesin was below 1% of the delivered dose.
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Cancer Chemother. Pharmacol. · Jan 1998
Effects of demographic variables on vorozole pharmacokinetics in healthy volunteers and in breast cancer patients.
Vorozole (VOR) is a selective nonsteroidal inhibitor of the cytochrome P450-dependent aromatase that catalyzes the conversion of androgens to estrogens. It is currently being developed as a therapeutic agent in the endocrine treatment of postmenopausal women with breast cancer. This work was aimed to explore the effects of demographic and other variables on VOR pharmacokinetics. ⋯ Healthy volunteer/patient, single/multiple dosing differences, and age were identified as the fixed effects influencing the CL of VOR. WT was the main determinant of distributional PK parameters. The peripheral and steady-state volumes of distribution were gender-dependent. In view of the relatively high degree of residual interpatient variability in CL, the slight effect of age on it is unlikely to be clinically significant.