Abstract
Purpose
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 nM (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).
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Van Hattumm AH, Pinedo HM, Schulper HM, Hausheer FH, Boven E (2000) New highly lipophilic BNP1350 is an effective drug in experimental human cancer. Int J Cancer 88:260–266
Maxwell Al, Gellert M (1986) Mechanistic aspects of DNA topoisomerases. Adv Protein Chem 38:69–107
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 30:623
Liu L (1989) DNA topoisomerase poisons as antitumor drugs. Annu Rev Biochem 58:351–375
Yao S, Murali D, Seetharamulu P, Haridas K, Petluru PN, Reddy DG, Hausheer FH (1998) Topotecan lactone selectively binds to double- and single-stranded DNA in the absence of topoisomerase I. Cancer Res 58:3782–3786
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 38:227
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 39:420
Kerr JZ, Berg SL, Hausheer FH, Blaney SM (1999) Karenitecins: cytotoxicity studies in pediatric tumor cell lines. Proc Am Assoc Cancer Res 40:112
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 40:111
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 40:113
Keir ST, Hausheer F, Lawless AA, Bigner DD, Friedman HS (2001) Therapeutic activity of 7-[(2-trimethylsilyl)]-20(S)-camptothecin against central nervous system tumor-derived xenografts in athymic mice. Cancer Chemother Pharmacol 48:83–87
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 53:725–727
Blaney SM, Takimoto C, Murry DJ, Kuttesch N, McCully C, Cole DE, Godwin K, Balis FM (1998) Plasma and cerebrospinal pharmacokinetics of 9-aminocamtothecin (9-AC), irinotecan (CPT-11), and SN-38 in nonhuman primates. Cancer Chemother Pharmacol 41:464–468
Wood JH, Poplack DG, Bleyer WA, Ommaya AK (1977) Primate model for long-term study of intraventricularly or intrathecally administered drugs and intracranial pressure. Science 195:499–501
Poplack DG, Bleyer WA, Wood JH, Kostolich M, Savitch JL, Ommaya AK (1977) A primate model for study of methotrexate pharmacokinetics in the central nervous system. Cancer Res 37(7 Pt 1):1982–1985
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 DC
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 40:520–525
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 759:117–124
Perrier D, Mayersohn M (1982) Noncompartmental determination of steady state volume of distribution for any mode of administration. J Pharm Sci 71:372–373
Knott GD (1979) MLAB: a mathematical modeling tool. Comput Programs Biomed 10:271–280
Author information
Authors and Affiliations
Corresponding author
Additional information
This work was supported in part by NICHD U01 HD37242.
Rights and permissions
About this article
Cite this article
Thompson, P.A., Berg, S.L., Aleksic, A. et al. Plasma and cerebrospinal fluid pharmacokinetic study of BNP1350 in nonhuman primates. Cancer Chemother Pharmacol 53, 527–532 (2004). https://doi.org/10.1007/s00280-004-0765-6
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00280-004-0765-6