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- Title
A phase I study of 9-aminocamptothecin as a colloidal dispersion formulation given as a fortnightly 72-h infusion.
- Authors
Leguizamo, Jorge; Quinn, Mary; Takimoto, Chris H.; Liang, Michael D.; Ismail, Abdel-Salam Attia; Pang, Janet; Dahut, William; Grem, Jean L.
- Abstract
Purpose. A phase I pharmacologic study was undertaken to determine the maximum tolerated dose (MTD), to characterize the pharmacokinetic profile, and to evaluate all toxicities of the aqueous colloidal dispersion formulation of 9-aminocampothecin (9-AC). Methods. 9-AC was administered as a constant 72-h i.v. infusion every 2 weeks to adult cancer patients at dose rates ranging from 25 to 59 μg/m2 per hour. Results. Twenty patients with refractory solid tumors received a total of 86 courses of 9-AC at four dose levels. Myelosuppression, particularly granulocytopenia, was the most common toxicity. Two of six assessable patients entered at 59 μg/m2 per hour had dose-limiting toxicity (grade 3 diarrhea or need for a 2-week treatment delay to permit granulocyte recovery), whereas lower doses were well tolerated. At the recommended dose, 47 μg/m2 per hour, the average steady-state plasma levels (Cpss) and area under the curve (AUC) of 9-AC lactone and total drug were 15 and 75 nM, and 1034 and 4220 nM·h, respectively. A moderate correlation was seen between 9-AC lactone AUC and the percentage decrease in granulocytes. Conclusions. The recommended phase II dose of 9-AC colloidal dispersion as a 72-h infusion every 14 days is 47 μg/m2 per hour (1.13 mg/m2 per day). The Cpss of 9-AC lactone at this dose exceeded the 10 nM threshold level for preclinical activity.
- Subjects
CANCER patients; LEUCOCYTES; ANTIVIRAL agents; CHEMICAL kinetics
- Publication
Cancer Chemotherapy & Pharmacology, 2003, Vol 52, Issue 4, p333
- ISSN
0344-5704
- Publication type
Article
- DOI
10.1007/s00280-003-0657-1