Pharmaceutical development of a parenteral formulation of the novel anti-tumor agent carzelesin (U-80,244)

Vries, Jantine D. Jonkman de; Graaff-Teulen, Marga J. A. de; Henrar, R.E.C.; Bosch, J. Jantina Kettenes van den; Bult, A.; Beijnen, Jos H.

doi:10.1007/bf00873045

Cited by 5 publications

(3 citation statements)

References 14 publications

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“…Shortly before intravenous infusion the PET formulation is diluted with 5% dextrose infusion solution, which increases the pH within physiologically accepted limits. 4 Influence of BufferssExperiments were performed where k obs was measured at varying buffer concentrations, while pH, ionic strength (µ ) 0.3) and temperature (25 or 60°C) were kept constant. Table 1 shows the influence of buffer ions on the degradation of carzelesin.…”

Section: Ln[carzelesin] T ) Ln[carzelesin] 0 -K Obs T (1)mentioning

confidence: 99%

“…5 A stable parenteral formulation of carzelesin in a polyethylene glycol 400 (PEG 400)/absolute ethanol/Tween 80 (6:3:1, v/v/v; PET formulation) solution was developed, 4 which is now being tested in phase I clinical trials. 6 During the manufacturing process of clinical batches of carzelesin in the PET formulation, observations were made indicating that the stability of the drug in this formulation was dependent upon the interbatch variability of the excipients used in the vehicle.…”

Section: Introductionmentioning

confidence: 99%

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Systematic Study on the Chemical Stability of the Prodrug Antitumor Agent Carzelesin (U-80,244)

Vries

Doppenberg

Henrar

et al. 1996

Journal of Pharmaceutical Sciences

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The chemical stability of the novel anticancer agent carzelesin in aqueous buffer/acetonitrile (1:1, v/v) mixtures has been investigated utilizing a stability-indicating reversed-phase high-performance liquid chromatographic assay. The degradation kinetics of carzelesin has been studied as a function of pH, buffer composition, ionic strength, and temperature. Degradation of carzelesin follows (pseudo-) first-order kinetics. A pH-rate profile, using rate constants extrapolated to zero buffer concentration, was constructed demonstrating that carzelesin is most stable in the pH region 1-4. The degradation rate of carzelesin was not significantly affected by buffer components and by the ionic strength. In addition to the formation of the degradation products U-76,073, U-76,074, and aniline in alkaline medium and in acetate buffer solution, another degradation product was formed in acetate buffer solution. In perchloric acid buffer solution (pH* < 3), U-76,073 and U-76,074 could not be detected as degradation products.

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Section: Ln[carzelesin] T ) Ln[carzelesin] 0 -K Obs T (1)mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Systematic Study on the Chemical Stability of the Prodrug Antitumor Agent Carzelesin (U-80,244)

Vries

Doppenberg

Henrar

et al. 1996

Journal of Pharmaceutical Sciences

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“…Therefore, the starting dose of this phase I trial was 24 µg m -2 . Carzelesin was supplied by Pharmacia & Upjohn Company (Kalamazoo, Michigan, USA) in 2-ml vials containing a drug concentration of 250 µg ml -1 in a non-aqueous vehicle, comprised of a 2:1 mixture of polyethylene glycol 400 and ethanol, with 10% Tween 80 (PET) (Jonkman-de Vries et al, 1994). This pharmaceutical preparation was kept frozen at -30°C and protected against light.…”

Section: Screening and Follow-up Studiesmentioning

confidence: 99%

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

et al. 1999

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Carzelesin is a cyclopropylpyrroloindole analogue which acts as a DNA-sequence-specific alkylating agent. In this phase I study, Carzelesin was given as a 4-weekly 10 min IV infusion to 51 patients with advanced solid tumours. Patients received a median of two courses (range 1–5) at one of nine dose levels: 24, 48, 96, 130, 150, 170, 210, 250 and 300 μg m −2 . According to NCI-CTC criteria, non-haematological toxicities (grade 1/2) included fever, nausea and vomiting, mucositis and anorexia, none of which was clearly dose related. The dose-limiting toxicity was haematological and consisted mainly of neutropenia and to a lesser extent thrombocytopenia. From the dose level 150 μg m −2 , the haematological toxicity (particularly thrombocytopenia) was delayed in onset, prolonged and cumulative in some patients. In several courses, double WBC nadirs occurred. The maximum tolerated dose for a single course was 300 μg m −2 . From the dose level 170 μg m −2 , the intended dose intensity could not be delivered to most patients receiving > 2 courses owing to cumulative haematological toxicity. The dose level with the best dose intensity for multiple courses was 150 μg m −2 . The pharmacokinetics of Carzelesin and its metabolites (U-76,073; U-76,074) have been established in 31 patients during the first course of treatment using a HPLC method. Carzelesin exhibited linear pharmacokinetics. The concentration of U-76,074 (active metabolite) extended above the lower limit of quantitation (1 ng ml −1 ) for short periods of time and only at the higher dose levels. There was no relationship between neutropenia and the AUC of the prodrug Carzelesin, but the presence of detectable plasma levels of the active metabolite U-76,074 was usually associated with a substantial decrease in ANC values. © 1999 Cancer Research Campaign

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

Tellingen

Punt

Awada

et al. 1998

Cancer Chemotherapy and Pharmacology

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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.

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Pharmaceutical development of a parenteral formulation of the novel anti-tumor agent carzelesin (U-80,244)

Cited by 5 publications

References 14 publications

Systematic Study on the Chemical Stability of the Prodrug Antitumor Agent Carzelesin (U-80,244)

Systematic Study on the Chemical Stability of the Prodrug Antitumor Agent Carzelesin (U-80,244)

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

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

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