Clinical pharmacology of the novel marine-derived anticancer agent Ecteinascidin 743 administered as a 1- and 3-h infusion in a phase I study
作者:
Charlotte van Kesteren,
Chris Twelves,
Angela Bowman,
Klaas Hoekman,
Luis López-Lázaro,
José Jimeno,
Cecilia Guzman,
Ron Mathôt,
Andrew Simpson,
Jan Vermorken,
John Smyth,
Jan Schellens,
Michel Hillebrand,
Hilde Rosing,
Jos Beijnen,
期刊:
Anti-Cancer Drugs
(OVID Available online 2002)
卷期:
Volume 13,
issue 4
页码: 381-393
ISSN:0959-4973
年代: 2002
出版商: OVID
关键词: ET-743;pharmacodynamics;pharmaco-kinetics;phase I study
数据来源: OVID
摘要:
Ecteinascidin 743 (ET-743) is an anticancer agent derived from the Caribbean tunicateEcteinascidia turbinata. In the present article, the pharmacokinetics and pharmacodynamics of ET-743 are described within a phase I study. Forty patients with solid tumors initially received ET-743 as a 1-h i.v. infusion every 21 days at nine dose levels (50–1100 μg/m2). The maximal tolerated dose (MTD) was 1100 μg/m2, with thrombocytopenia and fatigue as dose-limiting toxicities (DLTs). As this MTD was substantially lower than in parallel phase I studies, dose escalation continued using a prolonged, 3-h infusion. Thirty-two patients were entered at five dose levels (1000–1800 μg/m2). The MTD was 1800 μg/m2with pancytopenia and fatigue as DLTs. The recommended phase II dose was 1650 μg/m2given over 3 h at which 12 patients were treated. Pharmacokinetic monitoring was performed for both treatment schedules. Non-compartmental pharmacokinetic parameters at the recommended dose with the 3-h infusion were (mean value±SD): clearance 87±30 l/h and mean elimination half-life 26±7 h. Pharmacokinetics were linear at the dose range tested with this schedule. The percentage decrease in platelets, white blood cells and neutrophils correlated with the area under the plasma concentration versus time curve (AUC), dose and maximal plasma concentration (Cmax). Hepatic toxicity increased with dose, AUC andCmax. Administration of 1650 μg/m2ET-743 over 3 h seemed clinically feasible; pharmacokinetics were linear with this schedule. Hepatic and hematological toxicities correlated with exposure to ET-743.
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