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Clinical pharmacology of the novel marine-derived anticancer agent Ecteinascidin 743 administered as a 1- and 3-h infusion in a phase I study
van Kesteren, C.; Twelves, C.; Bowman, A.; Hoekman, K.; López-Lázaro, L.; Jimeno, J.; Guzman, C.; Mathôt, R.A.A.; Simpson, A.; Vermorken, J.B.; Smyth, J.; Schellens, J.H.; Hillebrand, M.J.X.; Rosing, H.; Beijnen, J.H. (2002). Clinical pharmacology of the novel marine-derived anticancer agent Ecteinascidin 743 administered as a 1- and 3-h infusion in a phase I study. Anti-Cancer Drugs 13(4): 381-393. dx.doi.org/10.1097/00001813-200204000-00007
In: Anti-Cancer Drugs. Lippincott Williams & Wilkins: Philadelphia. ISSN 0959-4973, more
Peer reviewed article  

Available in  Authors 

Keyword
    Marine
Author keywords
    ET-743; pharmacodynamics; pharmacokinetics; phase I study

Authors  Top 
  • van Kesteren, C.
  • Twelves, C.
  • Bowman, A.
  • Hoekman, K.
  • López-Lázaro, L.
  • Jimeno, J.
  • Guzman, C.
  • Mathôt, R.A.A.
  • Simpson, A.
  • Vermorken, J.B.
  • Smyth, J.
  • Schellens, J.H.
  • Hillebrand, M.J.X.
  • Rosing, H.
  • Beijnen, J.H.

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 iv. infusion every 21 days at nine dose levels (50-1100 mug/m(2)). The maximal tolerated dose (MTD) was 1100 mug/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 mug/m(2)). The MTD was 1800 mug/m(2) with pancytopenia and fatigue as DLTs. The recommended phase 11 dose was 1650 mug/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,,,. Administration of 1650 mug/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.

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