Cancer Chemotherapy and Pharmacology

, Volume 53, Issue 6, pp 527–532 | Cite as

Plasma and cerebrospinal fluid pharmacokinetic study of BNP1350 in nonhuman primates

  • Patrick A. Thompson
  • Stacey L. Berg
  • Alexander Aleksic
  • Jody Z. Kerr
  • Leticia McGuffey
  • Robert Dauser
  • Jed G. Nuchtern
  • Fred Hausheer
  • Susan M. Blaney
Original Article

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).

Keywords

BNP1350 Karenitecin Topoisomerase I inhibitor CSF penetration Pharmacokinetics 

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Copyright information

© Springer-Verlag 2004

Authors and Affiliations

  • Patrick A. Thompson
    • 1
  • Stacey L. Berg
    • 2
  • Alexander Aleksic
    • 2
  • Jody Z. Kerr
    • 2
    • 6
  • Leticia McGuffey
    • 2
  • Robert Dauser
    • 3
  • Jed G. Nuchtern
    • 4
  • Fred Hausheer
    • 5
  • Susan M. Blaney
    • 2
  1. 1.Department of PediatricsBaylor College of MedicineHoustonUSA
  2. 2.Texas Children’s Cancer CenterBaylor College of MedicineHoustonUSA
  3. 3.Department of NeurosurgeryBaylor College of MedicineHoustonUSA
  4. 4.Department of SurgeryBaylor College of MedicineHoustonUSA
  5. 5.BioNumerik Pharmaceuticals, IncSan AntonioUSA
  6. 6.Wyeth ResearchCollegevilleUSA

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