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.
Original language | English (US) |
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Pages (from-to) | 333-338 |
Number of pages | 6 |
Journal | Cancer Chemotherapy and Pharmacology |
Volume | 52 |
Issue number | 4 |
DOIs | |
State | Published - Oct 2003 |
Externally published | Yes |
Keywords
- Camptothecin
- Pharmacodynamics
- Pharmacokinetics
- Phase I
- Topoisomerase I
ASJC Scopus subject areas
- Oncology
- Toxicology
- Pharmacology
- Cancer Research
- Pharmacology (medical)