title: Pharmacokinetics and pharmacodynamics of the novel marine-derived anticancer agent ecteinascidin 743 in a phase I dose-finding study.
abstract: Ecteinascidin (ET) 743 is an anticancer agent derived from the Caribbean tunicate Ecteinascidia turbinata. Preclinical studies revealed activity of ET-743 against different tumor types. A Phase I clinical trial was designed with ET-743 to identify the maximum tolerated dose and dose-limiting toxicities (DLTs). Furthermore, the pharmacokinetics of ET-743 and relationships with pharmacodynamics were evaluated. Adult patients with solid, resistant tumors received ET-743 as a 24-h i.v. infusion every 21 days. Blood samples were obtained during the first treatment course and in several consecutive courses. Noncompartmental pharmacokinetic analysis was performed. Relationships between pharmacokinetics and hepatic and hematological toxicities were explored. Fifty-two patients were treated at nine dose levels (50-1800 microg/m2). The DLTs, neutropenia and thrombocytopenia, were experienced at 1800 microg/m2. Twenty-five patients were treated at the recommended Phase II dose of 1500 microg/m2. At this dose, the mean value +/- SD for total body clearance was 59 +/- 31 liters/h, and the mean t(1/2) was 89 +/- 41 h. Pharmacokinetics were linear over the dose range tested. Prior exposure to ET-743 did not alter the pharmacokinetics in subsequent courses. The percentage of decrease in WBC count and absolute neutrophil count was correlated to the area under the plasma concentration versus time curve (AUC). Hepatic toxicity, defined as rise in alanine aminotransferase and aspartate aminotransferase, increased with dose and AUC but was reversible and not dose limiting. In conclusion, ET-743 administered as a 24-h i.v. infusion at a dose of 1500 microg/m2 is clinically feasible; severe thrombocytopenia and neutropenia are the DLTs.
authors.affiliation: Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute/Slotervaart Hospital, Amsterdam. APCKS@SLZ.NL
authors.forename: C
authors.initials: C
authors.lastname: van Kesteren
authors.forename: E
authors.initials: E
authors.lastname: Cvitkovic
authors.forename: A
authors.initials: A
authors.lastname: Taamma
authors.forename: L
authors.initials: L
authors.lastname: López-Lázaro
authors.forename: J M
authors.initials: JM
authors.lastname: Jimeno
authors.forename: C
authors.initials: C
authors.lastname: Guzman
authors.forename: R A
authors.initials: RA
authors.lastname: Math t
authors.forename: J H
authors.initials: JH
authors.lastname: Schellens
authors.forename: J L
authors.initials: JL
authors.lastname: Misset
authors.forename: E
authors.initials: E
authors.lastname: Brain
authors.forename: M J
authors.initials: MJ
authors.lastname: Hillebrand
authors.forename: H
authors.initials: H
authors.lastname: Rosing
authors.forename: J H
authors.initials: JH
authors.lastname: Beijnen
mesh_terms: D000328:Adult; D000368:Aged; D000410:Alanine Transaminase / Q000378:metabolism; D018906:Antineoplastic Agents, Alkylating / Q000493:pharmacokinetics* / Q000494:pharmacology*; D019540:Area Under Curve; D001219:Aspartate Aminotransferases / Q000378:metabolism; D004149:Dioxoles / Q000493:pharmacokinetics* / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007546:Isoquinolines / Q000493:pharmacokinetics* / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D008956:Models, Chemical; D009369:Neoplasms / Q000188:drug therapy*; D009503:Neutropenia; D044005:Tetrahydroisoquinolines; D013921:Thrombocytopenia; D013997:Time Factors; D000077606:Trabectedin
chemical_list: D018906:Antineoplastic Agents, Alkylating; D004149:Dioxoles; D007546:Isoquinolines; D044005:Tetrahydroisoquinolines; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D000077606:Trabectedin