Phase I and pharmacokinetic study of the topoisomerase II catalytic inhibitor fostriecin

We conducted a phase I and pharmacokinetic study of the topoisomerase II catalytic inhibitor fostriecin. Fostriecin was administered intravenously over 60 min on days 1-5 at 4-week intervals. Dose was escalated from 2 mg m(-2) day(-1) to 20 mg m(-2) day(-1) in 20 patients. Drug pharmacokinetics was...

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Bibliographic Details
Published in:British journal of cancer 1999-02, Vol.79 (5-6), p.882-887
Main Authors: DE JONG, R. S, MULDER, N. H, UGES, D. R. A, SLEIJFER, D. T, HÖPPENER, F. J. P, GROEN, H. J. M, WILLEMSE, P. H. B, VAN DER GRAAF, W. T. A, DE VRIES, E. G. E
Format: Article
Language:English
Subjects:
Adult
Aged
Alanine Transaminase - blood
Alkenes - adverse effects
Alkenes - pharmacokinetics
Alkenes - toxicity
Antibiotics, Antineoplastic - adverse effects
Antibiotics, Antineoplastic - pharmacokinetics
Antibiotics, Antineoplastic - toxicity
Antineoplastic agents
Aspartate Aminotransferases - blood
Biological and medical sciences
Carcinoma, Non-Small-Cell Lung - drug therapy
Carcinoma, Small Cell
Chemotherapy
Colorectal Neoplasms - drug therapy
Dose-Response Relationship, Drug
Drug Resistance, Neoplasm
Female
Half-Life
Humans
Lung Neoplasms - drug therapy
Male
Medical sciences
Metabolic Clearance Rate
Middle Aged
Neoplasms - blood
Neoplasms - drug therapy
Pharmacology. Drug treatments
Polyenes
Pyrones
Regular
Teniposide - toxicity
Topoisomerase II Inhibitors
Tumor Cells, Cultured
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Summary:We conducted a phase I and pharmacokinetic study of the topoisomerase II catalytic inhibitor fostriecin. Fostriecin was administered intravenously over 60 min on days 1-5 at 4-week intervals. Dose was escalated from 2 mg m(-2) day(-1) to 20 mg m(-2) day(-1) in 20 patients. Drug pharmacokinetics was analysed with high performance liquid chromatography with UV-detection. Plasma collected during drug administration was tested in vitro for growth inhibition of a teniposide-resistant small-cell lung cancer (SCLC) cell line. The predominant toxicities were elevated liver transaminases (maximum common toxicity criteria (CTC) grade 4) and serum creatinine (maximum CTC grade 2). These showed only a limited increase with increasing doses, often recovered during drug administration and were fully reversible. Duration of elevated alanine-amino transferase (ALT) was dose-limiting in one patient at 20 mg m(-2). Other frequent toxicities were grade 1-2 nausea/vomiting, fever and mild fatigue. Mean fostriecin plasma half-life was 0.36 h (initial; 95% CI, 0-0.76 h) and 1.51 h (terminal; 95% CI, 0.41-2.61 h). A metabolite, most probably dephosphorylated fostriecin, was detected in plasma and urine. No tumour responses were observed, but the plasma concentrations reached in the patients were insufficient to induce significant growth inhibition in vitro. The maximum tolerated dose (MTD) has not been reached, because drug supply was stopped at the 20 mg m(-2) dose level. However, further escalation seems possible and is warranted to achieve potentially effective drug levels. Fostriecin has a short plasma half-life and longer duration of infusion should be considered.
ISSN:0007-0920
1532-1827
DOI:10.1038/sj.bjc.6690141