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Pharmacological particulars
Pharmacotherapeutic group: Antineoplastic and immunomodulating agents, immunosuppressants, calcineurin inhibitors, ciclosporin.
ATCvet code: QL04AD01.
Pharmacodynamic properties
Ciclosporin (also known as cyclosporin, cyclosporine, cyclosporine 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 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 of 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
The bioavailability of ciclosporin is about 35%. The peak plasma concentration is reached within 1 to 2 hours. The bioavailability is better and less subject to individual variations if ciclosporin is administered to fasted animals rather than at mealtimes.
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.
Unchanged ciclosporin represents about 25% of circulating blood concentrations in the course of the first 24 hours.
Ciclosporin is metabolised mainly in the liver by cytochrome P450 (CYP3A4), but also in the intestine. Metabolism takes place essentially in the form of hydroxylation and demethylation, leading to metabolites with little or no activity.
Elimination is mainly via the faeces. Only 10% is excreted in the urine, mostly in the form of metabolites.
No significant accumulation was observed in blood of dogs treated for one year.
The bioavailability of orally administered Ciclosporin is between 25 and 29% in cats. The peak blood concentrations is generally reached within 1 to 2 hours when given to fasted cats. Blood drug concentration-time curves are not dose proportional at dose levels greater than the recommended dose. There is a less than proportional increase in Cmax and AUC over the dose range 8 to 40 mg/kg.
The volume of distribution at steady state is about 1.7-2.1 L/kg.
Ciclosporin is metabolised in the liver by cytochrome P450 3A enzymes.
The terminal elimination phase half-life is 8-11 h.
There is no significant accumulation of ciclosporin beyond the first week of treatment.
In the cat, there are large inter-individual variations in blood ciclosporin concentrations. At the recommended dosage, ciclosporin plasma concentrations are not predictive of the clinical response, therefore monitoring of blood levels is not recommended.