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

Sridhar Mani, Lalitha Iyer, Linda Janisch, Xiaolin Wang, Gini F. Fleming, Richard L. Schilsky, Mark J. Ratain

Research output: Contribution to journalArticlepeer-review

22 Scopus citations

Abstract

Purpose: 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. Method: 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. Results: 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 C(max), and these parameters:showed a poor correlation with dose (r2 = 0.07 and 0.38, respectively). Conclusions: 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.

Original languageEnglish (US)
Pages (from-to)84-87
Number of pages4
JournalCancer Chemotherapy and Pharmacology
Volume42
Issue number1
DOIs
StatePublished - May 28 1998
Externally publishedYes

Keywords

  • 9-Aminocamptothecin
  • CD formulation
  • Oral
  • Pharmacokinetic
  • Phase I
  • Topoisomerase inhibitor

ASJC Scopus subject areas

  • Oncology
  • Toxicology
  • Pharmacology
  • Cancer Research
  • Pharmacology (medical)

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