Phase I/II pharmacokinetic study of mitoxantrone by continuous venous infusion in patients with solid tumours and lymphoproliferative diseases.
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/m2 per day and was increased by a 0.2 mg/m2 per day step dose. The main toxicity observed was leukopenia which became limiting in more than 50% of the patients receiving 2.4 mg/m2 per day (12 mg/m2 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] micrograms/1 at 2 mg/m2 per day, 2.56 [1.32] micrograms/1 at 2.2 per day and 3.46 [1.32] micrograms/l at 2.4 mg/m2 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] l/h/m2 and the volume of distribution of the beta phase averaged 2327 [2125] l/m2. 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.
de Forni
M
M
Centre Claudius Regaud, Toulouse, France.
Lachau
S
S
Huguet
F
F
Canal
P
P
Laurent
G
G
Chevreau
C
C
Roche
H
H
Bugat
R
R
D000293:Adolescent; D000328:Adult; D000368:Aged; D004341:Drug Evaluation; D005260:Female; D006402:Hematologic Diseases / Q000139:chemically induced; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D008942:Mitoxantrone / Q000008:administration & dosage / Q000097:blood / Q000633:toxicity*; D009369:Neoplasms / Q000097:blood* / Q000188:drug therapy
D008942:Mitoxantrone