Pharmacokinetics and toxicity of the novel oral demethylating agent zebularine in laboratory and tumor bearing dogs

Abstract

The purpose of this study was to determine the plasma pharmacokinetics (PK) and toxicity of zebularine, an oral cytidine analog with demethylating activity, in dogs. Plasma zebularine concentrations were determined by HPLC-MS/MS following an oral zebularine dose of 8 or 4 mg kg^-1 . Plasma zebularine clearance was constant. Mean maximum concentration (C_max ) was 23 ± 4.8 and 8.6 ± 1.4 µM following 8 and 4 mg kg^-1 , respectively. Mean half-life was 5.7 ± 0.84 and 7.1 ± 2.1 following 8 and 4 mg kg^-1 , respectively. A single 8 mg kg^-1 dose was well tolerated. Daily 4 mg kg^-1 treatment in three laboratory dogs resulted in grade 4 neutropenia (n = 3), grade 1 anorexia (n = 2) and grade 1 or 2 dermatologic changes (n = 2). All adverse events resolved with supportive care. A 4 mg kg^-1 dose every 21 days was well tolerated. A follow-up dose escalation study is in progress with a lower starting dose.

Keywords: DNA methylation; demethylating agent; dog pharmacokinetics and toxicity; epigeneitcs; zebularine.