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Plasma and Cerebrospinal Fluid Pharmacokinetics of Clofarabine in Nonhuman Primates

Authors' Affiliations: ¹ Texas Children's Cancer Center, Departments of ² Surgery and ³ Neurosurgery, Baylor College of Medicine, Houston, Texas; ⁴ Genzyme Oncology, San Antonio, Texas; and ⁵ Department of Veterinary Sciences, M.D. Anderson Cancer Center, Bastrop, Texas

Requests for reprints: Stacey Berg, Texas Children's Cancer Center, 6621 Fannin Street, MC3-3320 Houston, TX 77030. Phone: 832-824-4588; Fax: 832-825-4039; E-mail: sberg{at}txccc.org.

Introduction: Clofarabine (2-chloro-2'fluoro-2'-deoxy-9-ß-D-arabinofuranosyladenine) is a purine nucleoside analogue that is active in the treatment of acute leukemia. We studied the pharmacokinetics and cerebrospinal fluid penetration of clofarabine in a nonhuman primate model.

Methods: A dose of 2.3 mg/kg of clofarabine was given i.v. over 2 hours to each of four animals. Plasma and cerebrospinal fluid (CSF) samples were obtained at specified intervals and the clofarabine concentration determined by reverse-phase high-pressure liquid chromatography with mass spectroscopy.

Results: The median clofarabine clearance was 17 mL/min/kg (range, 15-20), the median plasma area under the concentration-time curve was 452 µmol/L minutes (range, 380-487), and the median terminal half-life was 105 minutes (range, 78-138). Concentrations of clofarabine in CSF could not be modeled reliably because the terminal rate constant was not well defined. The median CSF penetration was 5% (range, 3-26%).

Conclusion: Clofarabine penetrates into the CSF only modestly, but the concentrations obtained may approach those that are cytotoxic in vitro. Evaluation of the contribution of clofarabine to central nervous system preventive therapy should be considered in future studies.