Plasma and cerebrospinal fluid pharmacokinetic study of BNP1350 in nonhuman primates.
OBJECTIVE
BNP1350 (7-[(2-trimethylsilyl)ethyl]-20(S)-camptothecin, karenitecin), a highly lipophilic camptothecin, a high percentage of which is maintained in the active lactone form under physiologic conditions, has recently entered clinical trials in adults and children. BNP1350 has shown significant preclinical antitumor activity against a wide variety of adult and pediatric tumor cell lines. This study was undertaken to define the pharmacokinetics of BNP1350 in both plasma and cerebrospinal fluid (CSF) in a nonhuman primate model.


METHODS
Four nonhuman primates with indwelling Ommaya reservoirs received BNP1350, 0.1 mg/kg i.v, administered as a 60-min infusion. Frequent plasma and CSF samples were obtained for quantitation of BNP1350 concentrations using reverse-phase high-pressure liquid chromatography (HPLC).


RESULTS
Disappearance of the lactone form from the plasma was biexponential with a mean distribution half-life of 57.5 min (CV +/-33%) and an elimination half-life of 457 min (CV +/-24%). The volume of distribution for the central compartment was 1.36 l/kg (CV +/-27%) and clearance from the central compartment was 10.6 ml/kg per minute (CV +/-28%). The peripheral compartment volume of distribution was 1.96 l/kg (CV +/-8.4%). Peak CSF lactone concentration, which occurred at 12 to 25 min after the end of the infusion, was 0.33 n M (CV +/-71%).


CONCLUSIONS
The ratio of the CSF AUC to the plasma AUC was less than 5% (range 0.4% to 3.0%), similar to other highly protein-bound topoisomerase inhibitors such as 9-aminocamptothecin and SN-38 (the active metabolite of irinotecan).
Thompson
Patrick A
PA
Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
Berg
Stacey L
SL
Aleksic
Alexander
A
Kerr
Jody Z
JZ
McGuffey
Leticia
L
Dauser
Robert
R
Nuchtern
Jed G
JG
Hausheer
Fred
F
Blaney
Susan M
SM
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics; D019540:Area Under Curve; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics; D002408:Catheters, Indwelling; D007275:Injections, Intravenous; D008253:Macaca mulatta; D059004:Topoisomerase I Inhibitors
D000970:Antineoplastic Agents; D059004:Topoisomerase I Inhibitors; C406143:cositecan; D002166:Camptothecin