title: Clinical pharmacology of the novel marine-derived anticancer agent Ecteinascidin 743 administered as a 1- and 3-h infusion in a phase I study.
abstract: Ecteinascidin 743 (ET-743) is an anticancer agent derived from the Caribbean tunicate Ecteinascidia 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 microg/m(2)). The maximal tolerated dose (MTD) was 1100 microg/m(2), 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 microg/m(2)). The MTD was 1800 microg/m(2) with pancytopenia and fatigue as DLTs. The recommended phase II dose was 1650 microg/m(2) given 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 (C(max)). Hepatic toxicity increased with dose, AUC and C(max). Administration of 1650 microg/m(2) ET-743 over 3 h seemed clinically feasible; pharmacokinetics were linear with this schedule. Hepatic and hematological toxicities correlated with exposure to ET-743.
authors: Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute/Slotervaart Hospital, Amsterdam, The Netherlands. apcks@slz.nl
authors: Charlotte
authors: C
authors: van Kesteren
authors: Chris
authors: C
authors: Twelves
authors: Angela
authors: A
authors: Bowman
authors: Klaas
authors: K
authors: Hoekman
authors: Luis
authors: L
authors: López-Lázaro
authors: José
authors: J
authors: Jimeno
authors: Cecilia
authors: C
authors: Guzman
authors: Ron A A
authors: RA
authors: Mathôt
authors: Andrew
authors: A
authors: Simpson
authors: Jan B
authors: JB
authors: Vermorken
authors: John
authors: J
authors: Smyth
authors: Jan H M
authors: JH
authors: Schellens
authors: Michel J X
authors: MJ
authors: Hillebrand
authors: Hilde
authors: H
authors: Rosing
authors: Jos H
authors: JH
authors: Beijnen
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D019540:Area Under Curve; D004149:Dioxoles / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D006207:Half-Life; D006801:Humans; D007262:Infusions, Intravenous; D007546:Isoquinolines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D044005:Tetrahydroisoquinolines; D013921:Thrombocytopenia / Q000139:chemically induced; D013997:Time Factors; D000077606:Trabectedin; D014561:Urochordata / Q000737:chemistry
chemical_list: D018906:Antineoplastic Agents, Alkylating; D004149:Dioxoles; D007546:Isoquinolines; D044005:Tetrahydroisoquinolines; D000077606:Trabectedin