A clinical pharmacokinetics study of carzelesin given by short-term intravenous infusion in a phase I study

Cancer Chemotherapy and Pharmacology
O van TellingenJ H Beijnen

Abstract

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 lower limit of quantitation (LLQ) of the high-performance liquid chromatography (HPLC) method used in this study was 1 ng/ml for the parent drug and its metabolic products. Carzelesin was rapidly eliminated from plasma (elimination half-life 23 +/- 9 min; mean value +/- SD). At all dose levels, U-76,073 was found as early as in the first samples taken after the start of the infusion. However, the concentration of U-76,074 exceeded the LLQ for only short periods and only at the higher dose levels. Although the plasma levels of all three compounds were well above the respective IC50 values obtained by in vitro clonogenic assays, they were much lower than those observed in a preclinical study in mice. There was a substantial discrepancy in the mean plasma clearance observed between patients from insti...Continue Reading

Citations

Dec 19, 2002·Journal of the National Cancer Institute·Sharyn D BakerAlex Sparreboom
Aug 14, 2002·American Journal of Pharmacogenomics : Genomics-related Research in Drug Development and Clinical Practice·D A Anthoney, C J Twelves
May 6, 2010·Drug Metabolism Reviews·Federica VacondioBernard Testa
Mar 31, 2009·Cancer Treatment Reviews·Xuemei CaiDaniel D Von Hoff
Apr 3, 1999·British Journal of Cancer·A AwadaD J Wagener

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