title: A clinical and pharmacological study of high-dose mitozolomide given in conjunction with autologous bone marrow rescue.
abstract: In conjunction with autologous bone marrow rescue, high-dose mitozolomide was given i.v. to 16 patients with refractory malignancies at doses ranging from 100 to 400 mg/m2 over 1 h. Neutropaenia occurred consistently at 300 mg/m2, and three trivial infective episodes were recorded. Thrombocytopaenia occurred consistently at 150 mg/m2, and three patients experienced episodes of minor bleeding. The death of one subject was attributable to pulmonary thromboembolism during the bone marrow reinfusion. Transient emesis and mild alopecia were the only other toxicities. Three of six evaluable patients receiving greater than or equal to 300 mg/m2 exhibited measurable reductions in tumour dimensions, although these failed to fulfil the criteria for a partial response. Mitozolomide was undetectable in plasma at 12 h after drug administration. The plasma pharmacokinetic data fitted mono- or biexponential models in all patients. Model-independent pharmacokinetic parameters were: peak plasma drug concentration, 3.4-46 mg/l; AUC, 8-82 mg h l-1; clearance, 7.6-45 l/h; steady-state volume of distribution, 11-85 l; and plasma elimination half-life, 1.4-2.8 h. Dose-dependent pharmacokinetics were not observed, and only a small percentage of the delivered dose was eliminated unchanged in the urine. The maximally tolerated dose of mitozolomide given with autologous bone marrow rescue was greater than 400 mg/m2. At this dose myelosuppression was the only major toxicity, and the plasma drug levels and AUC values were comparable to those obtained after therapeutic doses in experimental models.
authors.affiliation: Department of Oncology, Wellington Hospital, New Zealand.
authors.forename: M
authors.initials: M
authors.lastname: McKeage
authors.forename: P
authors.initials: P
authors.lastname: Dady
authors.forename: M
authors.initials: M
authors.lastname: Clear
authors.forename: A
authors.initials: A
authors.lastname: MacDonald
mesh_terms: D000328:Adult; D000368:Aged; D016026:Bone Marrow Transplantation; D003131:Combined Modality Therapy; D005260:Female; D006207:Half-Life; D006801:Humans; D007958:Leukocyte Count; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D009588:Nitrogen Mustard Compounds / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D010976:Platelet Count
chemical_list: D009588:Nitrogen Mustard Compounds; C040369:mitozolomide