Oral cytarabine ocfosfate pharmacokinetics and assessment of leukocyte biomarkers in normal dogs

Abstract

Abstract Background Cytosine arabinoside (Ara‐C) is a nucleoside analog prodrug utilized for immunomodulatory effects mediated by its active metabolite Ara‐CTP. Optimal dosing protocols for immunomodulation in dogs have not been defined. Cytarabine ocfosfate (CO) is a lipophilic prodrug of Ara‐C that can be administered PO and provides prolonged serum concentrations of Ara‐C. Objectives Provide pharmacokinetic data for orally administered CO and determine accumulation and functional consequences of Ara‐CTP within peripheral blood leukocytes. Animals Three healthy female hound dogs and 1 healthy male Beagle. Methods Prospective study. Dogs received 200 mg/m2 of CO PO q24h for 7 doses. Serum and cerebrospinal fluid (CSF) CO and Ara‐C concentrations were measured by liquid chromatography‐tandem mass spectroscopy (LC‐MS/MS). Complete blood counts, flow cytometry, and leukocyte activation assays were done up to 21 days. Incorporation of Ara‐CTP within leukocyte DNA was determined by LC‐MS/MS. Results Maximum serum concentration (Cmax) for Ara‐C was 456.1‐724.0 ng/mL (1.88‐2.98 μM) and terminal half‐life was 23.3 to 29.4 hours. Cerebrospinal fluid: serum Ara‐C ratios ranged from 0.54 to 1.2. Peripheral blood lymphocyte concentrations remained within the reference range, but proliferation rates poststimulation were decreased at 6 days. Incorporation of Ara‐CTP was not saturated and remained >25% of peak concentration at 13 days. Conclusions and Clinical Importance Oral CO may produce prolonged serum Ara‐C half‐lives at concentrations sufficient to induce functional changes in peripheral leukocytes and is associated with prolonged retention of DNA‐incorporated Ara‐CTP. Application of functional and active metabolite assessment is feasible and may provide more relevant data to determine optimal dosing regimens for Ara‐C‐based treatments.

Keywords

• Ara‐C
• Ara‐CTP
• canine
• Cytosar
• HPLC
• prodrug