title: Phase I clinical and pharmacokinetic study of topotecan administered by a 24-hour continuous infusion.
abstract: OBJECTIVE
  To determine the maximum-tolerable dose (MTD) and to investigate the pharmacokinetics and pharmacodynamics of topotecan in a phase I study. Topotecan is a novel semisynthetic derivative of the anticancer agent camptothecin and inhibits the intranuclear enzyme topoisomerase I. Broad preclinical activity rationalized further clinical evaluation.
  
  
  METHODS
  In this phase I trial, topotecan was administered by 24-hour continuous infusion every 21 days to patients with solid malignant tumors.
  
  
  RESULTS
  A total of 25 eligible patients, of whom 22 were pretreated, entered the study. They received the following dosages of topotecan: 2.5, 3.75, 5.60, 8.4, and 10.5 mg/m2 by 24-hour infusion. Reversible leukopenia and thrombocytopenia were dose-limiting, with mild anemia occurring regularly. Other toxicities, such as alopecia, mucositis, nausea, and vomiting were sporadic and mild. Responses were not observed. However, eight patients had stable disease. The plasma concentration-time curves were not compatible with standard linear pharmacokinetic models, and indications were found for the occurrence of nonlinear (saturation) kinetics at the dosages studied.
  
  
  CONCLUSIONS
  The recommended dose for phase II studies is 8.4 mg/m2 when administered as a 24-hour infusion, which is well tolerated. Further studies will be necessary to account for the putative nonlinear behavior of the drug.
authors.affiliation: Department of Medical Oncology, Antoni van Leeuwenhoek Hospital, The Netherlands Cancer Institute, Amsterdam.
authors.forename: L J
authors.initials: LJ
authors.lastname: van Warmerdam
authors.forename: W W
authors.initials: WW
authors.lastname: ten Bokkel Huinink
authors.forename: S
authors.initials: S
authors.lastname: Rodenhuis
authors.forename: I
authors.initials: I
authors.lastname: Koier
authors.forename: B E
authors.initials: BE
authors.lastname: Davies
authors.forename: H
authors.initials: H
authors.lastname: Rosing
authors.forename: R A
authors.initials: RA
authors.lastname: Maes
authors.forename: J H
authors.initials: JH
authors.lastname: Beijnen
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D007970:Leukopenia / Q000139:chemically induced; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D009503:Neutropenia / Q000139:chemically induced; D013921:Thrombocytopenia / Q000139:chemically induced; D019772:Topotecan
chemical_list: D000970:Antineoplastic Agents; D019772:Topotecan; D002166:Camptothecin