Pharmacodynamics and pharmacokinetics of a 72-hour infusion of 9-aminocamptothecin in adult cancer patients.
OBJECTIVE
To investigate the pharmacokinetics and pharmacodynamics of 9-aminocamptothecin (9-AC) infused over 72 hours at doses of 5 to 74 micrograms/m2/h.


METHODS
9-AC lactone and total (lactone plus carboxylate) plasma concentrations were measured in 44 patients with solid tumors using a high-performance liquid chromatography (HPLC) assay. Fifteen patients underwent extended pharmacokinetic sampling to determine the distribution and elimination kinetics of 9-AC.


RESULTS
At steady-state, 8.7% +/- 4.7% (mean +/- SD) of the total drug circulated in plasma as the active 9-AC lactone. Clearance of 9-AC lactone was uniform (24.5 +/- 7.3 L/h/m2) over the entire dose range examined; however, total 9-AC clearance was nonlinear and increased at higher dose levels. In 15 patients treated at dose levels > or = 47 micrograms/m2/h, the volume of distribution at steady-state for 9-AC lactone was 195 +/- 114 L/m2 and for total 9-AC it was 23.6 +/- 10.6 L/m2. The elimination half-life was 4.47 +/- 0.53 hours for 9-AC lactone and 8.38 +/- 2.10 hours for total 9-AC. In pharmacodynamic studies, dose-limiting neutropenia correlated with steady-state lactone concentrations (Css) R2 = .77) and drug dose (R2 = .71).


CONCLUSIONS
Plasma 9-AC concentrations rapidly declined to low levels following the end of a 72-hour infusion and the mean fraction of total 9-AC circulating in plasma as the active lactone was less than 10%. The pharmacokinetics of 9-AC may have a great impact on its clinical activity and should be considered in the design of future clinical trials of this topoisomerase I inhibitor.
Takimoto
C H
CH
National Cancer Institute-Navy Medical Oncology Branch, Division of Clinical Sciences, National Cancer Institute, National Naval Medical Center, Bethesda, MD 20889-5105, USA. ctakim@helix.nih.gov
Dahut
W
W
Marino
M T
MT
Nakashima
H
H
Liang
M D
MD
Harold
N
N
Lieberman
R
R
Arbuck
S G
SG
Band
R A
RA
Chen
A P
AP
Hamilton
J M
JM
Cantilena
L R
LR
Allegra
C J
CJ
Grem
J L
JL
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D004334:Drug Administration Schedule; D005260:Female; D006207:Half-Life; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000097:blood* / Q000188:drug therapy*
D000970:Antineoplastic Agents; C080125:9-aminocamptothecin; D002166:Camptothecin