Pharmacokinetics of multivesicular liposomal encapsulated cytarabine when administered subcutaneously in dogs

• Published in: Journal of veterinary internal medicine Vol. 34; no. 4; pp. 1563 - 1569
• Main Authors: Vazquez Fuster, Irene B., Taylor, Amanda R., Smith, Annette N., Duran, Sue H., Ravis, William R., Jasper, Shanese L., Arnold, Robert D.
• Format: Journal Article
• Language: English
• Published: Hoboken, USA John Wiley & Sons, Inc 01-07-2020; Wiley
• Subjects: Administration, Intravenous - veterinary; Animals; Antimetabolites, Antineoplastic - administration & dosage; Antimetabolites, Antineoplastic - blood; Antimetabolites, Antineoplastic - pharmacology; canine; Catheters; Cell cycle; chemotherapy; Creatinine; Cross-Over Studies; cytarabine; Cytarabine - administration & dosage; Cytarabine - blood; Cytarabine - pharmacokinetics; cytosar; Cytotoxicity; Deoxyribonucleic acid; DepoCyt; DNA; Dogs; Dogs - blood; Dogs - metabolism; Drug dosages; Female; Injections, Subcutaneous - veterinary; Laboratory animals; leukemia; Liposomes - administration & dosage; Liposomes - pharmacokinetics; lymphoma; meningoencephalomyelitis of unknown etiology; Nervous system; Pharmacokinetics; Plasma; Random Allocation; SMALL ANIMAL; Studies; Veterinary colleges; Veterinary medicine; California; DepoCyt; meningoencephalomyelitis of unknown etiology; cytarabine; leukemia; lymphoma; pharmacokinetics; cytosar; canine; chemotherapy
• ISSN: 0891-6640; 1939-1676
• DOI: 10.1111/jvim.15809

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.