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


METHODS
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 Cmax, 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.
Mani
S
S
Department of Medicine, University of Chicago, IL, USA.
Iyer
L
L
Janisch
L
L
Wang
X
X
Fleming
G F
GF
Schilsky
R L
RL
Ratain
M J
MJ
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019540:Area Under Curve; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*
D000970:Antineoplastic Agents; C080125:9-aminocamptothecin; D002166:Camptothecin