Clinical pharmacology of the novel marine-derived anticancer agent Ecteinascidin 743 administered as a 1- and 3-h infusion in a phase I study.
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.
van Kesteren
Charlotte
C
Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute/Slotervaart Hospital, Amsterdam, The Netherlands. apcks@slz.nl
Twelves
Chris
C
Bowman
Angela
A
Hoekman
Klaas
K
López-Lázaro
Luis
L
Jimeno
José
J
Guzman
Cecilia
C
Mathôt
Ron A A
RA
Simpson
Andrew
A
Vermorken
Jan B
JB
Smyth
John
J
Schellens
Jan H M
JH
Hillebrand
Michel J X
MJ
Rosing
Hilde
H
Beijnen
Jos H
JH
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
D018906:Antineoplastic Agents, Alkylating; D004149:Dioxoles; D007546:Isoquinolines; D044005:Tetrahydroisoquinolines; D000077606:Trabectedin