Phase I/II pharmacokinetic study of mitoxantrone by continuous venous infusion in patients with solid tumours and lymphoproliferative diseases

Abstract

Phase I and pharmacokinetic studies were performed in order to evaluate the maximum tolerated dose and the efficiency of 120 h continuous venous infusion (CVI) of mitoxantrone. 25 patients suffering from either metastatic solid tumour or refractory lymphoproliferative disease were included in the study. The starting dose was 2 mg/m 2 per day and was increased by a 0.2 mg/m 2 per day step dose. The main toxicity observed was leukopenia which became limiting in more than 50% of the patients receiving 2.4 mg/m 2 per day (12 mg/m 2 over a 120 h period); this dose was defined as the maximal tolerated dose in these pretreated patients. One partial response and three stable diseases were observed. A plasma plateau concentration of mitoxantrone (2.13 [S.D. 0.54] μg/1 at 2 mg/m 2 per day, 2.56 [1.32] μg/1 at 2.2 mg/m 2 per day and 3.46 [1.32] μg/1 at 2.4 mg/m 2 per day) was reached within 24–48 h. It was linearly related to the administered dose. The mean plasma clearance of mitoxantrone was 27.8 [14.2] 1/h/m 2 and the volume of distribution of the β phase averaged 2327 [2125] l/m 2. An inverse relationship was established between the mitoxantrone clearance and the degree of hematologic toxicity. This 120 h CVI mitoxantrone schedule was safe and could be repeated every 3 weeks in an outpatient setting. The relationship between mitoxantrone clearance and the drug related haematotoxicity could be used for an individual dose adjustment.