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 journalArticle

22 Citations (Scopus)

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 - 1998
Externally publishedYes

Fingerprint

9-aminocamptothecin
Pharmacokinetics
Toxicity
Topoisomerase I Inhibitors
Intravenous Administration
Solubility
Nausea
Biological Availability
Area Under Curve
Oral Administration
Half-Life
Appointments and Schedules
Clinical Studies

Keywords

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

ASJC Scopus subject areas

  • Cancer Research
  • Pharmacology
  • Oncology

Cite this

Mani, S., Iyer, L., Janisch, L., Wang, X., Fleming, G. F., Schilsky, R. L., & Ratain, M. J. (1998). Phase I clinical and pharmacokinetic study of oral 9-aminocamptothecin (NSC-603071). Cancer Chemotherapy and Pharmacology, 42(1), 84-87. https://doi.org/10.1007/s002800050789

Phase I clinical and pharmacokinetic study of oral 9-aminocamptothecin (NSC-603071). / Mani, Sridhar; Iyer, Lalitha; Janisch, Linda; Wang, Xiaolin; Fleming, Gini F.; Schilsky, Richard L.; Ratain, Mark J.

In: Cancer Chemotherapy and Pharmacology, Vol. 42, No. 1, 1998, p. 84-87.

Research output: Contribution to journalArticle

Mani, S, Iyer, L, Janisch, L, Wang, X, Fleming, GF, Schilsky, RL & Ratain, MJ 1998, 'Phase I clinical and pharmacokinetic study of oral 9-aminocamptothecin (NSC-603071)', Cancer Chemotherapy and Pharmacology, vol. 42, no. 1, pp. 84-87. https://doi.org/10.1007/s002800050789
Mani, Sridhar ; Iyer, Lalitha ; Janisch, Linda ; Wang, Xiaolin ; Fleming, Gini F. ; Schilsky, Richard L. ; Ratain, Mark J. / Phase I clinical and pharmacokinetic study of oral 9-aminocamptothecin (NSC-603071). In: Cancer Chemotherapy and Pharmacology. 1998 ; Vol. 42, No. 1. pp. 84-87.
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