Cancer chemotherapy and pharmacology
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Cancer Chemother. Pharmacol. · Jan 1999
Comparative StudyComparative cytotoxicity and pharmacokinetics of antimelanoma immunotoxins containing either natural or recombinant gelonin.
Immunotoxins are a class of targeted therapeutic agents under development by various research groups. The murine monoclonal antibody designated ZME-018 recognizes a high molecular weight glycoprotein present on most human melanoma cells and biopsy specimens and has been utilized for clinical imaging studies in patients with melanoma. The plant toxin gelonin is a ribosome-inactivating protein (RIP) with n-glycosidase activity similar to that of ricin A chain. ⋯ Pharmacokinetic studies showed that the terminal-phase plasma half-life of ZME-RG was similar to that of ZME itself (42 h vs 50 h) and almost threefold higher than that of ZME-NG (11.5 h). The area under the concentration curve (Cxt) for ZME-RG was 50% lower than that for ZME due to an increased apparent volume of distribution (Vd(a)) but was almost tenfold higher than the Cxt for ZME-NG. These studies suggest that immunoconjugates comprising RG demonstrate identical in vitro cytotoxic effects to immunoconjugates produced with NG and immunotoxins with RG display improved in vivo pharmacodynamics and tissue distribution compared to immunotoxins containing NG.
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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
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.
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Cancer Chemother. Pharmacol. · Jan 1998
Practical implementation of a modified continual reassessment method for dose-finding trials.
We describe a practical, reliable, efficient dose-finding design for cytotoxic drugs applied in a multi-institutional setting. ⋯ Our experience demonstrates the feasibility of implementing this design in multi-institutional trials and the possibility of performing dose-finding studies that require fewer patients than conventional methods.