Plasma and cerebrospinal fluid pharmacokinetics of nelarabine in nonhuman primates.

Abstract

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.

• Authors: Stacey L Berg, Claudia Brueckner, Jed G Nuchtern, Robert Dauser, Leticia McGuffey, Susan M Blaney
• Journal: Cancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 59 Issue 6 Pg. 743-7 (May 2007) ISSN: 0344-5704 [Print] Germany
• PMID: 16953392 (Publication Type: Journal Article)

Chemical References

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

Topics

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