The pharmacokinetics of cytarabine administered subcutaneously, combined with prednisone, in dogs with meningoencephalomyelitis of unknown etiology

Abstract

The objective of this study was to describe the pharmacokinetics (PK) of cytarabine (CA) after subcutaneous (SC) administration to dogs with meningoencephalomyelitis of unknown etiology (MUE). Twelve dogs received a single SC dose of CA at 50 mg/m as part of treatment of MUE. A sparse sampling technique was used to collect four blood samples from each dog from 0 to 360 min after administration. All dogs were concurrently receiving prednisone (0.5-2 mg kg day ). Plasma CA concentrations were measured by HPLC, and pharmacokinetic parameters were estimated using nonlinear mixed-effects modeling (NLME). Plasma drug concentrations ranged from 0.05 to 2.8 μg/ml. The population estimate (CV%) for elimination half-life and Tmax of cytarabine in dogs was 1.09 (21.93) hr and 0.55 (51.03) hr, respectively. The volume of distribution per fraction absorbed was 976.31 (10.85%) ml/kg. Mean plasma concentration of CA for all dogs was above 1.0 μg/ml at the 30-, 60-, 90-, and 120-min time points. In this study, the pharmacokinetics of CA in dogs with MUE after a single 50 mg/m SC injection in dogs was similar to what has been previously reported in healthy beagles; there was moderate variability in the population estimates in this clinical population of dogs.

The pharmacokinetics of cytarabine administered at three distinct subcutaneous dosing protocols in dogs with meningoencephalomyelitis of unknown origin

“…The C max , T max , half‐life (T 1/2 ), area under the concentration versus time curve (AUC), and clearance averages for each dose are presented in Table . The T 1/2 of Ara‐C in this study ranged from 1.4–1.6 hr, which is similar to previous reports (Crook et al, ; Pastina et al, ; Scott‐Moncrieff et al, ). A single 200 mg/m 2 injection resulted in the greatest overall drug exposure (AUC) at 32,510 ng × hr/ml, with a linear relationship between dose and AUC (Figure ).…”

“…Reported side effects of Ara-C include bone marrow suppression, vomiting, and diarrhea. At the standard dose of 200 mg/m 2 , these side effects appear extremely uncommon (Menaut, Landart, Behr, Lanore, & Trumel, 2008;Pastina et al, 2018;Zarfoss et al, 2006). At chemotherapeutic doses of 600 mg/m 2 , mild thrombocytopenia (115,000-170,000 platelets/mm 3 ) was reported in dogs receiving an IV bolus (Scott-Moncrieff et al, 1991).…”

“…A single 50 mg/m 2 SQ dose has been evaluated in both healthy beagles and dogs with MUO and yielded similar maximum plasma concentration (C max ) and time to maximum plasma concentration (T max ) results. Mean plasma concentrations of Ara‐C were above 1 µg/ml (Crook et al, ; Pastina et al, ).…”

Low frequency of pre‐treatment and post‐treatment haematological abnormalities in dogs with non‐infectious meningoencephalitis treated with cytosine arabinoside and prednisolone

“…The incidence of haematological abnormalities in patients with a presumptive diagnosis of NIME is sparsely documented in the current veterinary literature 3 5–8 10–14 24. A unique aspect of this study is the review of the haematological findings at diagnosis of a group of patients with presumptive NIME subsequently treated with prednisolone and a standard dose of CA.…”

The bioavailability of cytarabine in dogs with meningoencephalitis of unknown etiology through iontophoresis and rectal delivery

“…Cytarabine (CA) has gained growing popularity in the treatment of immune-mediated diseases. Subcutaneous (SC) and intravenous (IV) routes of CA administration have been described in dogs (Crook et al, 2012;Pastina et al, 2018). However, other routes of CA administration have not been well investigated to determine if there are reasonable alternatives for effective delivery.…”