Pharmacokinetics and pharmacodynamics of the novel marine-derived anticancer agent ecteinascidin 743 in a phase I dose-finding study

Ecteinascidin (ET) 743 is an anticancer agent derived from the Caribbean tu nicate Ecteinascidia turbinata. Preclinical studies revealed activity of ET -743 against different tumor types, A Phase I clinical trial was designed w ith ET-743 to identify the maximum tolerated dose and dose-limiting toxicit ies (DLTs). Furthermore, the pharmacokinetics of ET-743 and relationships w ith pharmacodynamics were evaluated, Adult patients with solid, resistant t umors 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. Relations hips between pharmacokinetics and hepatic and hematological toxicities were explored, Fifty-two patients were treated at nine dose levels (50-1800 mug /m(2)). The DLTs, neutropenia and thrombocytopenia, were experienced at 180 0 mug/m(2), Twenty-five patients were treated at the recommended Phase II d ose of 1500 mug/m(2). At this dose, the mean value +/- SD for total body cl earance was 59 +/- 31 liters/h, and the mean t(1/2) was 89 +/- 41 h. Pharma cokinetics were linear over the dose range tested. Prior exposure to ET-743 did not alter the pharmacokinetics in subsequent courses, The percentage o f decrease in WBC count and absolute neutrophil count was correlated to the area under the plasma concentration versus time curve (AUC). Hepatic toxic ity, defined as rise in alanine aminotransferase and aspartate aminotransfe rase, 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 15 00 mug/m(2) is clinically feasible; severe thrombocytopenia and neutropenia are the DLTs.