Pharmacokinetic studies of 9-nitrocamptothecin on intermittent and continuous schedules of administration in patients with solid tumors.
OBJECTIVE
Oral administration of 9-nitrocamptothecin (9NC), and the formation of its metabolite 9-aminocamptothecin (9AC), may be associated with high interpatient and intrapatient variability. Therefore, we evaluated the plasma pharmacokinetics and urine recovery of 9NC administered on three different schedules as part of phase I and phase II studies.


METHODS
In phase I schedule A, 9NC was administered orally daily for 5 days per week for 2 weeks repeated every 4 weeks. On phase I schedule B, 9NC was administered daily for 14 days repeated every 4 weeks. In Phase II, 9NC was administered daily for 5 days during 8 weeks (one cycle). Serial blood samples were obtained on day 1 and day 10 or 11 for phase I studies, and day 1 and day 50 for the phase II study. Recovery of 9NC and 9AC in urine was evaluated on day 1 and day 10 or 11 in the phase I study. Area under the 9NC and 9AC plasma concentration vs time curves from 0 to 24 h (AUC0-24 h) were calculated using compartmental analysis.


RESULTS
The mean+/-SD 9NC lactone AUC0-24 h values on day 1 at the maximum tolerated dose of schedules A and B (2.43 and 1.70 mg/m2, respectively) and the phase II dose (1.5 mg/m2) were 78.9+/-54.4, 155.7+/-112.8, and 48.3+/-17.5 ng/ml.h, respectively. The mean+/-SD 9AC lactone AUC0-24 h values at these same doses of 9NC were 17.3+/-17.9, 41.3+/-16.6, and 31.3+/-12.8 ng/ml h, respectively. The ratios of 9NC lactone AUC0-24 h on day 10 or 11 to day 1 on phase I A and B were 1.27+/-0.68 and 1.73+/-1.56, respectively, and the ratios 9AC lactone AUC0-24 h on day 10 or 11 to day 1 on phase I A and B were 2.23+/-1.02 and 1.65+/-0.97, respectively. The recovery of 9NC and 9AC in the urine was <15%.


CONCLUSIONS
There was significant interpatient and intrapatient variability in the disposition of 9NC and 9AC. 9NC and 9AC undergo primarily nonrenal elimination.
Molecular Therapeutics and Drug Discovery Program, University of Pittsburgh Cancer Institute, PA 15213, Pittsburgh, USA.
Laura L
LL
Jung
Ramesh K
RK
Ramanathan
Merrill J
MJ
Egorin
Ruzhi
R
Jin
Chandra P
CP
Belani
Douglas M
DM
Potter
Sandra
S
Strychor
Donald L
DL
Trump
Christine
C
Walko
Marwan
M
Fakih
William C
WC
Zamboni
D000284:Administration, Oral; D002166:Camptothecin / Q000008:administration & dosage* / Q000031:analogs & derivatives* / Q000493:pharmacokinetics* / Q000652:urine; D004334:Drug Administration Schedule; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism*
C080125:9-aminocamptothecin; C079905:rubitecan; D002166:Camptothecin