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

Abstract

The objective of this study was to evaluate the pharmacokinetics of the standard cytarabine (Ara‐C) protocol (50 mg/m2 subcutaneously every 12 hr for 2 days) used for dogs with neuroinflammatory disease and compare it to two more practical protocols (a single 200 mg/m2 subcutaneous dose and two 100 mg/m2 subcutaneous doses every 12 hr). Four client‐owned dogs previously diagnosed with meningoencephalomyelitis of unknown origin were administered three distinct Ara‐C protocols with a 21‐day washout between each protocol. A complete blood count was performed seven days after each dosing protocol to assess for clinically relevant myelosuppression. No adverse events were observed. Plasma Ara‐C concentrations were measured using a validated liquid chromatography coupled to tandem mass spectrometry assay. The mean maximal concentrations in this study were 4,230, 9,293, and 16,675 ng/ml for a single dose of 50, 100, and 200 mg/m2, respectively. There was a linear relationship between dose and drug exposure. Drug exposure was similar regardless of the dosing protocol when the total dose was analyzed, with an area under the concentration versus time curve of 37,026, 38,465, and 32,510 ng × hr/ml for 50, 100, and 200 mg/m2, respectively.

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

“…This study demonstrates that when CA is administered via repeated subcutaneous injections over an 8‐h period, it achieves consistent and prolonged exposure in the plasma of dogs with MUE, exceeding 1 µg/ml throughout its course of administration. A proposed therapeutic target concentration of 1 µg/ml was applied in the present study, as has been applied in previous CA pharmacokinetic studies (Jones et al., 2019; Crook et al., 2013; Pastina et al., 2018; Early et al., 2016). This target has been extrapolated from the human literature in which passive diffusion of CA becomes significant only at concentrations greater than 1 µg/ml in sarcoma cells in vitro; however, the exact therapeutic target concentration in dogs has yet to be determined (Mulder & Harrap, 1975).…”

“…It has therefore been used for the treatment of multiple disease processes involving pathologic cell replication, including lymphoma (involving the bone marrow or central nervous system and in cases of relapse), leukaemia and optic neuritis of non‐infectious origin (Gillem et al., 2015; Marconato et al., 2008; LaRue et al., 2018; Pawlak et al., 2014, 2016; Bedos et al., 2020; Alvarez et al., 2006). As MUE is highly suspected to be due to a robust T‐cell autoimmune response, CA has been utilized as a treatment option for meningoencephalomyelitis of unknown aetiology (MUE) with the goal of inhibiting the pathologic lymphocyte proliferation associated with this autoimmune disease (Vitale et al., 2019). Based on its ability to cross the blood–brain barrier (BBB), favourable toxicity profile, capacity to exert cytotoxic effects in mitotically active cells, and consequentially improved survival times, CA has become a mainstay of treatment for MUE alongside glucocorticoids in recent years (Cornelis et al., 2019; Vitale et al., 2019; Menaut et al., 2008; Nuhsbaum et al., 2002; Lowrie et al., 2016; Scott Moncrieff et al., 1991; Behr et al., 2009; Zarfoss et al., 2006).…”

“…As MUE is highly suspected to be due to a robust T‐cell autoimmune response, CA has been utilized as a treatment option for meningoencephalomyelitis of unknown aetiology (MUE) with the goal of inhibiting the pathologic lymphocyte proliferation associated with this autoimmune disease (Vitale et al., 2019). Based on its ability to cross the blood–brain barrier (BBB), favourable toxicity profile, capacity to exert cytotoxic effects in mitotically active cells, and consequentially improved survival times, CA has become a mainstay of treatment for MUE alongside glucocorticoids in recent years (Cornelis et al., 2019; Vitale et al., 2019; Menaut et al., 2008; Nuhsbaum et al., 2002; Lowrie et al., 2016; Scott Moncrieff et al., 1991; Behr et al., 2009; Zarfoss et al., 2006).…”

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

“…Repeat dosing of 50 mg/m 2 and 100 mg/m 2 , for 2 doses or 1 dose, respectively, increased the overall time the plasma concentration of CA was more than 1 μg/mL over the course of treatment. 21 This yielded approximately the same AUC for each dosing protocol. 21 CA plasma concentrations greater than 1 μg/mL were attained intermittently with SC bolus dosing, but steady-state concentrations in this range were not achieved.…”

“…20 Therefore, sustained concentrations in the blood, such as those produced by an IV CRI or the Omnipod's SC CRI, encourage uptake into the brain and may provide optimal delivery to and effects upon the CNS. Jones et al 21 determined that SC boluses of CA at doses of 50 mg/m 2 , 100 mg/m 2 , and 200 mg/ m 2 could all achieve CA plasma concentrations greater than 1 μg/mL, although the concentration declined quickly after Cmax, and then for 6 to 10 hours it was maintained only at more than 0.1 μg/mL, depending on the dose. Repeat dosing of 50 mg/m 2 and 100 mg/m 2 , for 2 doses or 1 dose, respectively, increased the overall time the plasma concentration of CA was more than 1 μg/mL over the course of treatment.…”