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

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.

Perspectives on pharmacologic strategies in the management of meningoencephalomyelitis of unknown origin in dogs.

There are many non-infectious inflammatory diseases, assumed to be immune-mediated in origin, recognized to affect the nervous system in canine patients. Concentrating on meningoencephalomyelitis of unknown origin, we will discuss the medications used to treat the underlying disease process, focusing on their adverse effects, therapeutic monitoring when necessary and effectiveness. The literature overwhelmingly supports the use of a steroid/ Cytosar® or steroid/ cyclosporine treatment protocol with the steroid tapered after the acute phase of the disease, leaving the secondary medication to control the disease long term. The decision on when and how quickly to taper the steroid is clinician dependent as a best practices has not been established in the literature. Also discussed will be the supportive care treatments often needed in the acute phase of these patients' diagnosis and treatment such as anti-edema and anti-epileptic agents.

Cytarabine-Induced Encephalitis.

Teaching Point: Central nervous system adverse effects of cytarabine treatment include aseptic meningitis, myelopathy, and more rarely, encephalopathy, seizures, and cerebellar dysfunction. This case illustrates a cytarabine-induced encephalitis with predominant cerebellar involvement.

Pharmacokinetics of multivesicular liposomal encapsulated cytarabine when administered subcutaneously in dogs.

BACKGROUND: Prolonged cytotoxic concentrations of cytarabine (CA) are required for maximum cytotoxicity. DepoCyt is a human liposomal cytarabine (LC) product that lasts longer in plasma and CSF compared with free CA (FC). The use of LC has not been evaluated in dogs. OBJECTIVES: To perform a LC pharmacokinetic (PK) study when administered SC in dogs. ANIMALS: Five healthy female beagles. METHODS: Three-period, 3-treatment, nonblinded, randomized, and crossover design, including a pilot study. LC was administered at 50 mg/m2 SC and FC was administered at 25 and 50 mg/m2 SC and IV. Plasma CA concentrations were measured until 240, 72, and 8 hours after SC LC, SC FC, and IV FC administration, respectively. CA plasma concentrations were quantitated by ultra-high-performance liquid chromatography with mass spectrometry (MS/MS) detection and concentration-time profiles were evaluated by noncompartmental analysis. RESULTS: Subcutaneous LC administration resulted in a maximum plasma concentration of 26.3 to 59.78 ng/mL, time to reach maximum plasma concentration of 2 hours, area under the concentration-time curve to last measurable concentration of 669.3 to 1126 h × ng/mL, and plasma bioavailability (%F) of 19.6% to 31.3%. The PK profiles of FC after SC and IV administration differed when compared with LC. CONCLUSIONS AND CLINICAL IMPORTANCE: In healthy dogs, SC LC administration at 50 mg/m2 results in measurable plasma CA concentrations, is apparently safe and well tolerated, but does not result in prolonged cytotoxic plasma concentrations. Poor absorption of LC prevented establishment of a complete LC PK profile.

Cytosine arabinoside constant rate infusion without subsequent subcutaneous injections for the treatment of dogs with meningoencephalomyelitis of unknown origin.

BACKGROUND: The administration of cytosine arabinoside (CA) by continuous rate infusion (CRI) at the time of diagnosis has been shown to improve the 3-month survival of dogs diagnosed with meningoencephalomyelitis of unknown origin (MUO), compared to subcutaneous administration. The benefit of administering subsequent sequential CA subcutaneous injections is unknown. This study compares the outcomes of a CA CRI protocol with (CRI+subcutaneous group) or without (CRI group) follow-up CA subcutaneous injections; both groups received adjunctive prednisolone. METHODS: Forty-two dogs diagnosed with MUO were recruited (CRI group) and compared with 41 historical control dogs (CRI+subcutaneous group) in a prospective, controlled clinical trial with 36 months of follow-up. RESULTS: Success rates were respectively 64.3 per cent and 65 per cent in the CRI and the CRI+subcutaneous groups at 40 weeks following diagnosis, and 32.5 per cent and 35.9 per cent at 36 months following diagnosis. The median time to relapse was 299 and 285 days for the CRI and the CRI+subcutaneous groups, respectively. No statistically significant difference was found (P≥0.05). CONCLUSION: No clear benefit was identified in the administration of subsequent sequential CA subcutaneous injections after the first administration of CA by CRI for the treatment of dogs diagnosed with MUO.