Phase I clinical and pharmacokinetic study of oral 9-aminocamptothecin (NSC-603071)

9-Aminocamptothecin (9-AC) is a topoisomerase I inhibitor with high antitumor activity but poor solubility in conventional vehicles. The purpose of this study was to evaluate the toxicities and pharmacokinetics of a colloidal dispersion (CD) formulation of 9-AC when administered orally on a 5 days p...

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Bibliographic Details
Published in:Cancer chemotherapy and pharmacology 1998, Vol.42 (1), p.84-87
Main Authors: MANI, S, IYER, L, JANISCH, L, XIAOLIN WANG, FLEMING, G. F, SCHILSKY, R. L, RATAIN, M. J
Format: Article
Language:English
Subjects:
Adult
Aged
Antineoplastic agents
Antineoplastic Agents - administration & dosage
Antineoplastic Agents - pharmacokinetics
Antineoplastic Agents - therapeutic use
Area Under Curve
Biological and medical sciences
Camptothecin - administration & dosage
Camptothecin - analogs & derivatives
Camptothecin - pharmacokinetics
Camptothecin - therapeutic use
Chemotherapy
Female
Humans
Male
Medical sciences
Middle Aged
Neoplasms - drug therapy
Pharmacology. Drug treatments
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Summary:9-Aminocamptothecin (9-AC) is a topoisomerase I inhibitor with high antitumor activity but poor solubility in conventional vehicles. The purpose of this study was to evaluate the toxicities and pharmacokinetics of a colloidal dispersion (CD) formulation of 9-AC when administered orally on a 5 days per week every 2 weeks schedule. This formulation, which was developed for intravenous administration, was orally administered in 20 ml orange juice. A group of 16 cancer patients were treated at doses of 0.2-0.68 mg/m2 daily. Grade 1-2 nausea (n = 9) was common, usually occurring during the last 2 days of dosing. No objective responses or cumulative toxicities were observed. Pharmacokinetic analysis of total 9-AC showed highly variable apparent oral 9-AC clearance and half-life. There was marked interpatient variability at each dose level in the 9-AC AUC and Cmax, and these parameters showed a poor correlation with dose (r2 = 0.07 and 0.38, respectively). We conclude that this formulation is not suitable for further clinical development because of poor bioavailability and highly variable and/or saturable absorption or elimination. Another formulation developed for oral administration is under study elsewhere.
ISSN:0344-5704
1432-0843
DOI:10.1007/s002800050789