A busy clinician's review of cyclosporine


A busy clinician's review of cyclosporine

This oral immunosuppressive drug used to treat canine atopy is probably already in your armamentarium. But do you know which formulation to avoid, how obesity affects the dose, or when to decrease the dosage?
May 01, 2008

Most familiar as a drug used to prevent organ transplant rejection, cyclosporine has gained popularity over the last two decades in treating inflammatory skin diseases in both people and animals. It can be difficult to keep the vast available information straight. With this article, we want to give you the need-to-know information about cyclosporine's mechanism of action, pharmacokinetics, and adverse effects and how cyclosporine can be used in companion animals with atopic dermatitis, sebaceous adenitis, and perianal fistula.


Cyclosporine is a potent immunosuppressive agent that modulates the adaptive immune system. At doses indicated for dermatologic conditions, cyclosporine has anti-inflammatory effects on various leukocytes.1,2

By binding to cyclophilin (an intracellular receptor), cyclosporine inhibits the activity of calcineurin, a key enzyme in T cell activation. Calcineurin inhibition results in impaired cytokine transcription, namely of interleukin-2, interleukin-4, and alpha-interferon, thereby inhibiting activation of helper and cytotoxic T lymphocytes, macrophages, and monocytes.1-3

Decreased cytokine production subsequently inhibits activation of various inflammatory cells. Cyclosporine impairs mast cell and eosinophil production and survivability, and it impairs mast cell degranulation. Activation and proliferation of most T lymphocytes are decreased, thereby modulating the humoral and cell-mediated immune system. The number of Langerhans cells may be decreased in patients receiving cyclosporine, leading to decreased antigen presentation by these epidermal dendritic cells.1,2 In addition, cyclosporine alters keratinocyte function, leading to diminished cytokine production. A decrease in keratinocyte proliferation has also been noted in vitro; however, the clinical relevance of this finding is unknown.2


The pharmacokinetics of cyclosporine depends on the formulation (modified vs. unmodified) and on the patient's species. Concurrent medications and a patient's weight also influence cyclosporine's effects.


For dermatologic conditions, oral formulations are preferred, specifically the microemulsion (modified) forms (Atopica—Novartis Animal Health, Neoral—Novartis Pharmaceuticals) since they have improved absorption in animals. Unmodified formulations (e.g. Sandimmune—Novartis Pharmaceuticals, generic cyclosporine capsules) have poor bioavailability and extreme variability in their treatment efficacy in animals,4 so we do not recommend them.

The pharmacokinetics of modified cyclosporine (5 mg/kg orally daily) was studied in normal fasted beagles. Peak blood concentrations were reached after a mean of 1.4 hours, and the terminal half-life was determined to be roughly 9.4 hours. Based on these findings, once-daily dosing was deemed sufficient.5


Species differences also account for variability in cyclosporine metabolism and distribution. In dogs, hepatic metabolism is rapid, and the drug is primarily concentrated in tissue (skin, liver, kidneys, fat). In rats, however, hepatic metabolism is much slower, and cyclosporine is concentrated in the plasma and tissues, which increases rats' susceptibility to hepatotoxicosis and nephrotoxicosis.4 Less is known about the specific pharmacokinetics of cyclosporine in cats.

Concurrent medications

Marked individual variation in peak and trough cyclosporine concentrations has been noted in both people and dogs.4 Since cyclosporine is primarily metabolized by the cytochrome P-450 enzymes in the liver, hepatic function likely plays an important role in that variation. Concurrently administering other medications that also are metabolized by the hepatic P-450 enzyme system (e.g. ketoconazole) may alter cyclosporine concentrations in the blood. This effect may be clinically useful as concurrent administration of ketoconazole and cyclosporine often allows for a lower dose of cyclosporine to be administered with similar clinical effects.3,4 However, administer cyclosporine with care in dogs receiving medications primarily metabolized by cytochrome P-450 (e.g. ketoconazole, diltiazem, cimetidine, phenobarbital, rifampin) for other conditions. Closely monitor hepatic function in these patients.4


Obesity may also influence the pharmacokinetics of cyclosporine in various species. The concentration in adipose tissue and the hydrophobic nature of the compound lend support to dosing based on a patient's ideal weight rather than its actual weight.4,6