title: A phase I pharmacokinetic study of 21-day continuous infusion mitoxantrone.
abstract: A phase I study of mitoxantrone given as a continuous infusion for 21 days using a venous access port and a portable pump was performed. The first dose step was 0.3 mg/m2/d for 21 days. Courses were repeated every 6 weeks. Dose increment per step was 0.1 mg/m2/d in the first three dose steps and 0.2 mg/m2/d in the latter dose steps. Twenty-five patients entered the study and received a total of 50 courses, with a median of two courses (range, one to five). Up to 0.5 mg/m2/d, no toxicity (according to the World Health Organization [WHO] criteria) occurred. At 0.7 mg/m2/d, one patient experienced grade 2 leukocytopenia and at the 0.9 mg/m2/d dose step, one patient experienced grade 2 leukocytopenia, grade 1 thrombocytopenia, and grade 1 hair loss. At 1.1 mg/m2/d, two of six patients had grade 3 leukocytopenia, and in one patient treatment was discontinued after two days because of myocardial infarction. In both patients receiving 1.3 mg/m2/d, treatment was discontinued after 2 weeks because of grade 3 leukocytopenia. Three patients at the 1.1 mg/m2/d, dose step and two patients at the 1.3 mg/m2/d dose step experienced some nausea in the last week of the infusion period. One patient developed subclavian vein thrombosis. No infectious complications occurred. Pharmacokinetic studies were performed by high-performance liquid chromatography (HPLC) with ultraviolet (UV) detection. Plasma steady-state was reached after 35 hours. During steady-state there was a linear relationship between the mitoxantrone dose administered and the level of mitoxantrone in plasma (r = .93, P less than .005). The mitoxantrone level in leukocytes increased significantly during the infusion period at the 0.9 mg/m2, the 1.1 mg/m2, and the 1.3 mg/m2 dose steps. The area under the curve (AUC) in leukocytes was higher with continuous infusion of 1.1 mg/m2/d for 21 days compared with bolus injection of 12 mg/m2. Mitoxantrone could be detected in plasma for at least five days after the end of the 21-day infusion period and in leukocytes for at least 14 days. Continuous infusion mitoxantrone may increase intracellular drug uptake as expressed by intracellular AUC. We recommend a dose of 1.1 mg/m2/d for 3 weeks for evaluation of antitumor efficacy in phase II studies.
authors.affiliation: Department of Internal Medicine, University Hospital, Groningen, The Netherlands.
authors.forename: J
authors.initials: J
authors.lastname: Greidanus
authors.forename: E G
authors.initials: EG
authors.lastname: de Vries
authors.forename: N H
authors.initials: NH
authors.lastname: Mulder
authors.forename: D T
authors.initials: DT
authors.lastname: Sleijfer
authors.forename: D R
authors.initials: DR
authors.lastname: Uges
authors.forename: B
authors.initials: B
authors.lastname: Oosterhuis
authors.forename: P H
authors.initials: PH
authors.lastname: Willemse
mesh_terms: D000328:Adult; D000368:Aged; D004334:Drug Administration Schedule; D004341:Drug Evaluation; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D007958:Leukocyte Count; D007962:Leukocytes / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D008942:Mitoxantrone / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics; D009369:Neoplasms / Q000188:drug therapy*
chemical_list: D008942:Mitoxantrone