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Pharmacokinetics and Pharmacodynamics of the Novel Marine-derived Anticancer Agent Ecteinascidin 743 in a Phase I Dose-finding Study¹

Charlotte van Kesteren¹, Esteban Cvitkovic, Adelkrim Taamma, Luis López-Lázaro, Joe M. Jimeno, Cecilia Guzman, Ron A. A. Mathôt, Jan H. M. Schellens, Jean-Louis Misset, Etienne Brain, Michael J. X. Hillebrand, Hilde Rosing and Jos H. Beijnen

Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute/Slotervaart Hospital, 1066 EC, Amsterdam, the Netherlands [C. v. K., R. A. A. M., J. H. M. S., M. J. X. H., H. R., J. H. B.]; Paul Brousse Hospital, 94804 Villejuif Cedex, France [E. C., A. T., J. L. M., E. B.]; and Pharma Mar, Clinical Research and Development, 28760 Tres Cantos (Madrid), Spain [L. L-L., J. M. J., C. G.]

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 µg/m²). The DLTs, neutropenia and thrombocytopenia, were experienced at 1800 µg/m². Twenty-five patients were treated at the recommended Phase II dose of 1500 µg/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 µg/m² is clinically feasible; severe thrombocytopenia and neutropenia are the DLTs.

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