Topoisomerase I/II inhibitor intoplicine administered as a 24 h infusion: phase I and pharmacologic study.
Intoplicine, an antitumor drug which interacts with both topoisomerase enzymes I and II, has demonstrated a broad spectrum of activity in preclinical studies. This indicates further clinical evaluation. In the present phase I study, with the primary objective to determine the maximum tolerated dose, intoplicine was administered by a 24 h continuous infusion every 21 days to 32 patients with solid malignant tumors. The patients received 12-640 mg/m2 by a central venous catheter. Liver toxicity was dose limiting. One patient died in a hepatic coma after the first course (dose 640 mg/m2), which was associated with intoplicine treatment. Other side effects were sporadic and mild. Myelotoxicity was virtually absent. Twenty-two patients had stable disease for four to six courses of treatment. The plasma concentration-time curves were compatible with standard linear pharmacokinetic models, with a protracted terminal half-life (mean 115 h). Although one sudden death occurred probably due to intoplicine toxicity, we nevertheless feel that research with intoplicine should continue, mainly because of its preclinical activity and its unique mechanism of action. The recommended dose for phase II studies with intoplicine administered as a 24 h infusion is 384 mg/m2. Liver toxicity, also seen in studies employing other dosages and infusion durations, should be investigated extensively in further clinical studies.
van Gijn
R
R
Division of Medical Oncology, Section of Pharmacology, The Netherlands Cancer Institute/Slotervaart Hospital, Amsterdam, The Netherlands. aprvg@slz.nl
ten Bokkel Huinink
W W
WW
Rodenhuis
S
S
Vermorken
J B
JB
van Tellingen
O
O
Rosing
H
H
van Warmerdam
L J
LJ
Beijnen
J H
JH
D000328:Adult; D000368:Aged; D000740:Anemia / Q000139:chemically induced; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006207:Half-Life; D006501:Hepatic Encephalopathy / Q000139:chemically induced; D006801:Humans; D007211:Indoles / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D007262:Infusions, Intravenous / Q000009:adverse effects; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D010689:Phlebitis / Q000209:etiology; D011725:Pyridines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors; D000637:Transaminases / Q000187:drug effects / Q000378:metabolism; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D007211:Indoles; D011725:Pyridines; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors; D000637:Transaminases; C081834:intoplicine