Pharmacokinetics of a cytosine arabinoside subcutaneous protocol in dogs with meningoencephalomyelitis of unknown aetiology

Abstract

Cytosine arabinoside (CA) is a commonly used treatment for dogs with meningoencephalomyelitis of unknown aetiology (MUE) with various proposed protocols, many requiring 24 hours (h) of hospitalization or two visits within 24 h. This is a unidirectional study evaluating the pharmacokinetics of a CA subcutaneous (SC) protocol and a standard constant rate infusion (CRI) protocol in 8 dogs with MUE. Dogs received the CRI (200 mg/m2 IV over 24 h), followed by a SC protocol (50 mg/m2 every 2 h for 4 treatments) four weeks later. Plasma CA concentrations were measured by high‐pressure liquid chromatography–tandem mass spectrometry (HPLC‐MS). Median peak CA concentration for the SC protocol (3.40 µg/ml, range 1.60–9.70 µg/ml) was significantly higher than the CRI (1.09 µg/ml, range 0.77–1.67 µg/ml; p = .02). Median concentration at 1h and 8h following initiation of treatment was significantly higher for the SC protocol (CA1 2.28 µg/ml, range 0.97–2.67; CA8 1.83 µg/ml, range 0.77–2.84) compared to the CRI (CA1 0.01 µg/ml, range 0–0.45; CA8 0.74 µg/ml, range 0.67–1.11; p = .01). While the PK properties of CA when administered as a CRI has been previously investigated, this study demonstrated that CA when administered via repeated 50 mg/m2 injections every 2 h over an 8‐h period, provided sustained plasma levels above its therapeutic target and for a significantly longer duration of time than did a standard CRI protocol.

Novel subcutaneous cytarabine infusion with the Omnipod system in dogs with meningoencephalomyelitis of unknown etiology

“…When plasma concentrations of CA were compared between groups, the Cmax was greater in the SC group for the initial 8 hours of drug administration, but greater in the IV CRI group from 12 to 24 hours after treatment initiation. 19 Although the SC administration yielded a greater Cmax in that study, 19 the IV CRI maintained a more sustained peak plasma concentration. The mean plasma concentration of our study was greater than 1 μg/mL from 4 to 10 hours after initiation of the 8-hour infusion, which was longer than the maintenance of a similar plasma concentration in the SC bolus group in the study by Levitan et al 19 Although the mean plasma concentration in our study dropped to less than 1 μg/mL after 10 hours, it is likely that a longer infusion with the Omnipod device could also result in a prolonged steady-state concentration comparable to a 24-hour IV CRI.…”

“…Furthermore, in that study, the mean total AUC from IV CRI was 22.58 μg X hour/mL (SD, 3.19 μg X h/mL). Levitin et al 19 administered CA as an IV CRI in dogs with MUE at a rate of 8.33 mg/m 2 /hour over 24 hours (total dose, 200 mg/m 2 ), which produced a Cmax and AUC of 1.09 μg/mL and 15.74 μg X hour/ mL, respectively. They did not calculate Tmax in their study.…”

“…Lowrie et al 10 determined that IV CRI administration of CA (100 mg/m 2 over 24 h) showed significantly greater 3-month survival rates in MUE patients compared to dogs receiving SC bolus administration of CA (50 mg/m 2 SC q 12 h for 2 doses), which may represent the advantage of the IV CRI effects on the CNS resulting from sustained concentrations in the blood. In addition, Levitin et al 19 compared CA administration in 2 groups of dogs with MUE using either 4 SC boluses of 50 mg/m 2 every 2 hours or a 24-hour IV CRI of 200 mg/m 2 . When plasma concentrations of CA were compared between groups, the Cmax was greater in the SC group for the initial 8 hours of drug administration, but greater in the IV CRI group from 12 to 24 hours after treatment initiation.…”

New insights into the treatment of meningoencephalomyelitis of unknown origin since 2009: A review of 671 cases

“…Lastly, there is also the question of whether the administered dose of cytarabine was sufficiently high to achieve therapeutically useful blood levels. This specific issue has been examined in many recent publications but, specifically, it was shown that 200 mg/m 2 [double the dose used in ( 55 )] CRI cytarabine over 24 h was unreliable at producing durable blood levels above 1μg/mL (the presumed therapeutic level) ( 64 ). Nevertheless, whether the efficacy of cytarabine is time- (above threshold) or concentration-dependent is still not established.…”

Erratum

“…In the article by Levitin HA, (2021), Hilary A. Levitin is listed as the corresponding author in the published version.…”