Pharmacokinetics and bioavailability of oral 9-aminocamptothecin capsules in adult patients with solid tumors.
Preclinical studies indicate enhanced antitumor activity of 9-amino-20(S)-camptothecin (9-AC) when it is administered in a manner that provides prolonged systemic exposure. In view of this observation, the pharmacokinetics and oral bioavailability of 9-AC polyethylene glycol 1000 capsules were evaluated in 12 patients with solid tumors. Patients were randomized to receive either 1.5 mg/m2 9-AC p.o. on day 1 and 1.0 mg/m2 9-AC i.v. on day 8 or vice versa. Serial plasma samples were collected up to 55 h after dosing and analyzed for 9-AC by liquid chromatography. Plasma concentrations of the lactone and carboxylate forms of 9-AC rapidly reached an equilibrium, with the active lactone accounting for < 10% of total drug at the terminal disposition phase. The drug demonstrated peak levels at 1.2 h and an overall bioavailability of 48.6+/-17.6% (range, 24.5-80.4%), indicating significant systemic exposure to the drug, which may enable chronic oral treatment.
Sparreboom
A
A
Department of Medical Oncology, Rotterdam Cancer Institute, University Hospital Rotterdam, The Netherlands. sparreboom@onch.azr.nl
de Jonge
M J
MJ
Punt
C J
CJ
Nooter
K
K
Loos
W J
WJ
Porro
M G
MG
Verweij
J
J
D000284:Administration, Oral; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001682:Biological Availability; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D002214:Capsules; D004334:Drug Administration Schedule; D006801:Humans; D007275:Injections, Intravenous; D007408:Intestinal Absorption; D008875:Middle Aged; D009369:Neoplasms / Q000378:metabolism*
D000970:Antineoplastic Agents; D002214:Capsules; C080125:9-aminocamptothecin; D002166:Camptothecin