1. Oral cytarabine ocfosfate pharmacokinetics and assessment of leukocyte biomarkers in normal dogs
- Author
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Zwueste, Danielle M, Vernau, Karen M, Vernau, William, Pypendop, Bruno H, Knych, Heather K, Rodrigues, Carlos A, Kol, Amir, Questa, Maria, and Dickinson, Peter J
- Subjects
Veterinary Sciences ,Agricultural ,Veterinary and Food Sciences ,Ara-C ,Ara-CTP ,Cytosar ,HPLC ,canine ,prodrug ,Veterinary sciences - Abstract
BackgroundCytosine 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.ObjectivesProvide pharmacokinetic data for orally administered CO and determine accumulation and functional consequences of Ara-CTP within peripheral blood leukocytes.AnimalsThree healthy female hound dogs and 1 healthy male Beagle.MethodsProspective 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.ResultsMaximum 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 importanceOral 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.
- Published
- 2023