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Title:Pharmacokinetics of a novel cytosine arabinoside subcutaneous protocol in dogs with meningoencephalomyelitis of unknown etiology
Author(s):Levitin, Hilary A.
Advisor(s):Foss, Kari D
Contributor(s):Hague, Devon W; Reinhart, Jennifer M; Fan, Timothy M
Department / Program:Vet Clinical Medicine
Discipline:VMS-Veterinary Clinical Medcne
Degree Granting Institution:University of Illinois at Urbana-Champaign
chemotherapy, immunosuppression
Abstract:Meningoencephalomyelitis of unknown etiology (MUE) is an umbrella term used to describe a group of noninfectious inflammatory central nervous system (CNS) diseases in dogs. There are many subtypes of MUE identified in the canine population, including granulomatous meningoencephalomyelitis, necrotizing meningoencephalitis, necrotizing leukoencephalitis, steroid responsive meningitis arteritis, eosinophilic meningoencephalomyelitis, and greyhounds non-suppurative meningoencephalitis. The etiology of MUE remains unknown, but it is suspected to have an autoimmune pathogenesis. Emerging research points to genetic and environmental factors that are likely to play a role as well. Because histopathology from brain biopsy or necropsy is required for definitive diagnosis, antemortem diagnostic guidelines have been published in the literature. Treatment with glucocorticoids remain the standard of care for these patients. The prognosis is fair to guarded, with improved survival times when more than one immunomodulatory drug (IMD) is utilized. One IMD, cytosine arabinoside (CA), has been applied to dogs with MUE due to its ability to cross the blood brain barrier, low incidence of adverse effects, and prolonged survival times reported. In spite of its increasing application for dogs with MUE, there is no standard administration protocol for CA. Various protocols have been proposed, all requiring either 24-48 hours (h) of hospitalization or one prolonged day of hospitalization lasting longer than 12h. Thus, a study was designed to investigate the pharmacokinetic (PK) properties of CA when administered as repeated subcutaneous injections over an 8h period to dogs with MUE in order to determine if this amenable administration protocol is a viable alternative to more laborious CRI administration. The primary objective was to describe PK parameters of CA when administered SC over 8h and when administered as a CRI over 24h. The secondary objective was to determine if CA concentrations reach its therapeutic target (> 1 µg/mL) with both routes of administration. The final objective was to report the short term outcome of each patient 3 months following initiation of treatment. We hypothesized that both routes of administration would result in CA concentrations that exceeded its therapeutic target concentration at 1h and 8h following initiation of treatment, indicative of the proposed SC protocol providing sustained plasma CA concentrations throughout administration. Additionally, we hypothesize that most dogs receiving this protocol would have a favorable outcome, with the majority being alive 3 months after initiating treatment receiving only 1 oral IMD (either prednisone or prednisolone). Dogs with MRI and CSF findings compatible with an antemortem diagnosis of MUE weighing greater than 2.5 kilograms were recruited for this study, and 8 dogs met the inclusion criteria. Dogs received CA as a CRI (200 mg/m2 IV over 24h) initially, followed by a SC protocol (50 mg/m2 every 2h for 4 treatments) four weeks later. Plasma CA concentrations were measured by high-pressure liquid chromatography-tandem mass spectrometry (HPLC-MS). For both the IV and SC protocols, PK parameters were calculated including maximum plasma concentration (Cmax), observed area under the curve (AUC0-24) using the trapezoidal method, plasma concentrations at 1h and 8h after initiating treatment (C1 and C8, respectively), and duration of time plasma concentration exceeded 1 µg/mL (T>1). Time to Cmax (Tmax) was calculated for the SC protocol only. Wilcoxon sign rank tests were performed to compare Cmax, C1, C8, and T>1 between the CRI and SC protocols. McNemar's tests were used to compare the number of dogs that achieved plasma concentrations greater than 1 µg/mL at 1h and 8h following CA administration between the two administration protocols. Median peak CA concentration for the SC protocol (3.40 µg/mL, range 1.60-9.70 µg/mL) were significantly higher than the CRI (1.09 µg/mL, range 0.77-1.67 µg/mL; P = 0.02). Cmax following SC administration were significantly higher than when administered as a CRI, with a median of 3.4 µg/mL (range: 1.6-9.7 µg/mL) and 1.09 (range: 0.77-1.69 µg/mL; P = 0.0156), respectively. 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 = 0.01). T>1 was also significantly higher for the SC protocol (9.25h, range: 4.5-10.5) than for the CRI protocol (3.13h, range: 0-9.75; P = 0.039). Five of the 8 dogs remained alive at the time of follow-up 3 months later, and only 1 of these 5 dogs was receiving more than one oral IMD at that time (aside from prednisone or prednisolone). This study demonstrated that CA when administered as repeated SC injections over an 8h period achieved consistent and prolonged exposure in the plasma of dogs with MUE. Cytosine arabinoside (CA) exceeded its target concentration of 1 µg/mL at 1h and 8h following initiation of treatment via the proposed SC protocol, rarely meeting this target with the CRI protocol administered. These findings indicate further research investigating the therapeutic target of CA in dogs with MUE. Additionally, further research is warranted to determine if there is a significant difference in prognosis for dogs receiving the proposed SC protocol at the time of diagnosis when compared to more laborious CRI administration. Based on currently available data, the authors recommend the following protocol for CA in dogs with MUE: CA 100-200 mg/m2 intravenously as a CRI over 24h at the time of diagnosis, followed by 50 mg/m2 every 2 hours for 4 doses every 4 weeks. This SC protocol can be administered on an outpatient basis, reducing prolonged hospitalization or repeated hospital visits for treatment, reducing cost to the client, and most importantly, reducing pain to the patient by eliminated the indication for repeated intravenous catheterization.
Issue Date:2020-12-22
Rights Information:Copyright 2021 Hilary Levitin
Date Available in IDEALS:2021-09-17
Date Deposited:2021-05

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