Plasma and cerebrospinal fluid pharmacokinetic study of BNP1350 in nonhuman primates
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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.
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).
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 nM (CV ±71%).
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).
KeywordsBNP1350 Karenitecin Topoisomerase I inhibitor CSF penetration Pharmacokinetics
- 3.Johnston RK, McCabe FL, Faucette LF, Hertzberg RP, Kingsbury WD, Boehm JC, Caranfa MJ, Holden KG (1989) SK&F 104864, a water soluble analog of camptothecin with broad-spectrum activity in preclinical tumor models. Proc Am Assoc Res 30:623Google Scholar
- 6.Hausheer FH, Haridas K, Zhao M, Murali D, Seetharamulu P, Yao S, Reddy D, Pavankumar P, Saxe J, Qiuli H, Rustum Y (1997) Karenitecins: a novel class of orally active highly lipophilic topoisomerase I inhibitors. Proc Am Assoc Cancer Res 38:227Google Scholar
- 7.Hausheer FH, Haridas K, Zhao M, Murali D, Seetharamulu P, Yao S, Reddy D, Pavankumar P, Wu M, Saxe J, Huang Q, Rustum Y (1998) Karenitecins (part II): a novel class of orally active highly lipophilic topoisomerase I inhibitors. Proc Am Assoc Cancer Res 39:420Google Scholar
- 8.Kerr JZ, Berg SL, Hausheer FH, Blaney SM (1999) Karenitecins: cytotoxicity studies in pediatric tumor cell lines. Proc Am Assoc Cancer Res 40:112Google Scholar
- 9.Hausheer FH, Cao, S, Kanter P, Haridas K, Zhao M, Murali D, Seetharamulu P, Yao S, Reddy D, Pavankumar P, Saxe J, Huang Q, Chen X, Parker A, Wu M, Martinez N, Rustum Y (1999) Karenitecins: new preclinical developments with BNP1350 a novel highly potent lipophilic camptothecin. Proc Am Assoc Cancer Res 40:111Google Scholar
- 10.Boven E, Van Hattum A, Schulper H, Erkelens C, Hausheer FH, Pinedo H (1999) BNP1350 is a novel topoisomerase inhibitor with high efficacy when given by oral route. Proc Am Assoc Cancer Res 40:113Google Scholar
- 12.Blaney SM, Cole DE, Godwin K, Sung C, Poplack DG, Balis FM (1993) Plasma and cerebrospinal fluid pharmacokinetic study of topotecan in nonhuman primates. Cancer Res 53:725–727Google Scholar
- 16.National Institutes of Health (1988) Guide for the care and use of laboratory animals (Department of Health, Education, and Welfare Publication 85-123, revised). US Government Printing Office, Washington DCGoogle Scholar
- 17.McCully CL, Balis FM, Bacher J, Phillips J, Poplack DG (1990) A rhesus monkey model for continuous infusion of drugs into cerebrospinal fluid. Lab Anim Sci 40:520–525Google Scholar
- 18.Smith JA, Hausheer F, Newman RA, Madden TL (2001) Development of a high-performance liquid chromatographic method to determine the concentration of karenitecin, a novel highly lipophilic camptothecin derivative, in human plasma and urine. J Chromatogr B Biomed Sci Appl 759:117–124CrossRefPubMedGoogle Scholar