Plasma and cerebrospinal fluid pharmacokinetics of nelarabine in nonhuman primates

Cancer Chemother Pharmacol. 2007 May;59(6):743-7. doi: 10.1007/s00280-006-0328-0. Epub 2006 Sep 5.


Introduction: Nelarabine is a water-soluble prodrug of the cytotoxic deoxyguanosine analog ara-G, to which it is rapidly converted in vivo by adenosine deaminase. Nelarabine has shown activity in the treatment of T-cell malignancies, especially T-cell acute lymphoblastic leukemia. Preliminary data suggested that nelarabine might penetrate into the CSF. We therefore studied the CSF penetration of nelarabine and ara-G in a nonhuman primate model that has been highly predictive of anticancer drug distribution in humans.

Methods: Nelarabine (35 mg/kg, approximately 700 mg/m2) was administered over 1 h through a surgically implanted central venous catheter to four nonhuman primates. Blood (four animals) and ventricular CSF (three animals) samples were obtained at intervals for 24 h for determination of nelarabine concentrations, which were measured by HPLC-mass spectrometry.

Results: The nelarabine plasma AUC (median+/-s.d.) was 2,820+/-1,140 microM min and the ara-G plasma AUC was 20,000+/-8,100 microM min. The terminal half-life of nelarabine in plasma was 25+/-5.2 min and clearance was 42+/-61 ml/min/kg. The terminal half-life of ara-G in plasma was 182+/-45 min. In CSF the terminal half-life of nelarabine was 77+/-28 min and of ara-G was 232+/-79 min. The AUCcsf:AUCplasma was 29+/-11% for nelarabine and 23+/-12% for ara-G.

Conclusion: The excellent CSF penetration of nelarabine and ara-G supports further study of the contribution of nelarabine to the prevention and treatment of CNS leukemia.

MeSH terms

  • Animals
  • Antineoplastic Agents / blood*
  • Antineoplastic Agents / cerebrospinal fluid*
  • Arabinonucleosides / blood*
  • Arabinonucleosides / cerebrospinal fluid*
  • Chromatography, High Pressure Liquid
  • Macaca mulatta
  • Male
  • Mass Spectrometry
  • Prodrugs / pharmacokinetics


  • Antineoplastic Agents
  • Arabinonucleosides
  • Prodrugs
  • 9-arabinofuranosylguanine
  • nelarabine