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

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 institution 1 (7.9 +/- 2.1 l h[-1] m[-2]) and those from institution 2 (18.4 +/- 13.6 l h[-1] m[-2]; P = 0.038), probably reflecting problems with drug administration in the latter institution. 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.

Phase I study of Carzelesin (U-80,244) given (4-weekly) by intravenous bolus schedule

“…The results of the pharmacokinetic behaviour of Carzelesin and its major metabolites have been reported in detail elsewhere (Van Tellingen et al, 1998). In summary, the analytical method was sufficiently sensitive to establish a plasma concentration-time profile of Carzelesin from the first dose level of 24 µg m -2 (Van Tellingen et al, 1994a).…”

“…A detailed report of the clinical pharmacokinetics of Carzelesin has been previously reported (Van Tellingen et al, 1998). In short, the pharmacokinetics have been established in 31 patients enrolled in this phase I study with at least two patients per dose level sampled during their first course of chemotherapy.…”

Use of KW-2189, a DNA Minor Groove-Binding Agent, in Patients with Hepatocellular Carcinoma: A North Central Cancer Treatment Group (NCCTG) Phase II Clinical Trial

“…Subsequently analogs of CC-1065, including adozelesin, bizelesin, and carzelesin, were developed and have been evaluated in phase I-II clinical trials. [17][18][19][20][21][22][23][24][25] Hematologic toxicity, particularly neutropenia and thrombocytopenia, was dose limiting in the phase I trials. [18,19,21,22,24,25] The onset of hematologic toxicity tends to be delayed and prolonged.…”

DNA: Still A Target Worth Aiming At?

“…[62] The biphasic pattern of myelosuppression may result from different progenitor cells being targeted by the same drug, or different metabolites of the drug. [62] The biphasic pattern of myelosuppression may result from different progenitor cells being targeted by the same drug, or different metabolites of the drug.…”

“…[58] Carzelesin is rapidly converted in vivo into its active metabolite (U-76,074) via an intermediate metabolite (U-76,073). [62] A phase II clinical trial of carzelesin, given as a single 10 minute IV infusion of 150 μg/m 2 every 28 days in patients with relapsed solid tumors, has been reported in abstract form. [62] These levels are significantly less than achieved in mice at the maximum tolerated dose (MTD).…”