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Pharmacological particulars
Pharmacotherapeutic group: Immunosuppressants; Calcineurin inhibitors; Ciclosporin.
ATCvet code: QL04AD01
Pharmacodynamic properties
Ciclosporin (also known as ciclosporin A, CsA) is a selective immunosuppressor. It is a cyclic polypeptide consisting of 11 amino acids, has a molecular weight of 1203 daltons and acts specifically and reversibly on T lymphocytes.
Ciclosporin exerts anti-inflammatory and antipruritic effects in the treatment of allergic or atopic dermatitis. Ciclosporin has been shown to preferentially inhibit the activation of T-lymphocytes on antigenic stimulation by impairing the production of IL-2 and other T-cell derived cytokines. Ciclosporin also has the capacity to inhibit the antigen-presenting function on the skin immune system. It likewise blocks the recruitment and activation of eosinophils, the production of cytokines by keratinocytes, the functions of Langerhans cells, the degranulation of mast cells and therefore the release of histamine and pro-inflammatory cytokines.
Ciclosporin does not depress haematopoiesis and has no effect on the function of phagocytic cells.
Pharmacokinetic properties
Dogs: The bioavailability of ciclosporin is about 35% in dogs. The peak plasma concentration is reached within 1 hour. The bioavailability is better and less subject to individual variations if ciclosporin is administered to fasted animals rather than at mealtimes.
Cats: The bioavailability of ciclosporin administered to cats fasted for 24 hours (mixed with a small amount of food) or just after feeding was 29% and 23% respectively. The peak plasma concentration is generally reached within 1-2 hours when given to fasted cats. After oral administration of ciclosporin via the food to fasted cats, peak plasma concentrations were reached within 1.5-5 hours. The absorption can be delayed by several hours when given after feeding. In spite of differences in the pharmacokinetics of the drug given mixed with food or directly into the mouth of fed cats, it has been shown that the same clinical response is obtained.
Dogs: In dogs, the volume of distribution is about 7.8 L/kg. Ciclosporin is widely distributed to all tissues. Following repeated daily administration to dogs, ciclosporin concentration in the skin is several times higher than in blood.
Cats: In cats, the volume of distribution at steady state is about 3.3 L/kg. Ciclosporin is widely distributed to all tissues, including the skin.
Ciclosporin is metabolised mainly in the liver by cytochrome P450 (CYP 3A 4), but also in the intestine. Metabolism takes place essentially in the form of hydroxylation and demethylation, leading to metabolites with little or no activity.
Unchanged ciclosporin represents about 25% of circulating blood concentrations in the course of the first 24 hours in dogs.
Elimination is mainly via the faeces. A small portion of the administered dose is excreted in the urine as inactive metabolites. In dogs, elimination half-life ranges from about 10-20 hours. No significant accumulation was observed in blood of dogs treated for one year. In cats, a slight bioaccumulation related to the long half-life of the drug (approximately 24 hours) is observed with repeated dosing. The steady state in cats is reached within 7 days, with a bioaccumulation factor in the range of 1.0-1.72 (typically 1-2).
In cats, there are large inter-individual variations in plasma concentrations. At the recommended dosage, ciclosporin plasma concentrations are not predictive of the clinical response, therefore monitoring of blood levels is not recommended.