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Alterations in activated T-cell cytokine expression in healthy dogs over the initial 7 days of twice daily dosing with oral cyclosporine

Caitlin Riggs, Lakshmi Narayanan, Charlee Mulligan, Robert Wills, Andrew Mackin, Claire Fellman, John Thomason, Todd Archer
Journal of Veterinary Pharmacology and Therapeutics 2019 April 1
Cyclosporine is a powerful T-cell inhibitor used in the treatment of immune-mediated and inflammatory diseases in the dog. There is limited information on how to best monitor patients on cyclosporine therapy. Currently, pharmacokinetic and pharmacodynamic assays are available. Pharmacokinetic assays that measure the concentration of cyclosporine in the blood are used to assess if an appropriate drug concentration has been achieved; however, target blood drug concentrations have not been shown to reliably correlate with suppression of T-cell function in the dog. In human transplant recipients, therapeutic drug monitoring has shifted to include pharmacodynamic-based monitoring. Our laboratory has validated a RT-qPCR assay to measure the pharmacodynamic effects of cyclosporine in the dog. In this study, activated T-cell expression of IL-2 and IFN-γ was measured using RT-qPCR daily for 7 consecutive days in 8 healthy Walker hounds receiving oral cyclosporine at a dosage of 10 mg/kg every 12 hr. Cytokine production was found to be markedly decreased within 24 hr after the initiation of cyclosporine and remained significantly decreased for the duration of the project. Based on these results, cyclosporine causes a rapid drop in T-cell cytokine production that is sustained with continued dosing in healthy dogs. Although performed in healthy dogs, this study demonstrated a marked decrease in cytokine suppression within 24 hr of drug administration, suggesting that pharmacodynamic monitoring of cyclosporine's effects on T cells could be considered within several days of commencing therapy in dogs suffering from life-threatening immune-mediated disorders.


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