Source of information: Drugbank (External Link). Last updated on: 3rd July 18
*Trade Name used in the content below may not be the same as the HSA-registered product.
Active Ingredient / Synonyms
Ciclosporin | Ciclosporina | Ciclosporine | Ciclosporinum | CsA | CyA | Cyclosporin | Cyclosporin A | Cyclosporine |
A cyclic undecapeptide from an extract of soil fungi. It is a powerful immunosupressant with a specific action on T-lymphocytes. It is used for the prophylaxis of graft rejection in organ and tissue transplantation. Cyclosporine is produced as a metabolite by the fungus species Cordyceps militaris. (From Martindale, The Extra Pharmacopoeia, 30th ed).
For treatment of transplant (kidney, liver, and heart) rejection, rheumatoid arthritis, severe psoriasis.
Mechanism of Action
Cyclosporine binds to cyclophilin. The complex then inhibits calcineurin which is normally responsible for activating transcription of interleukin 2. Cyclosporine also inhibits lymphokine production and interleukin release. In ophthalmic applications, the precise mechanism of action is not known. Cyclosporine emulsion is thought to act as a partial immunomodulator in patients whose tear production is presumed to be suppressed due to ocular inflammation associated with keratoconjunctivitis sicca.
Used in immunosuppression for prophylactic treatment of organ transplants, cyclosporine exerts specific and reversible inhibition of immunocompetent lymphocytes in the G0-or G1-phase of the cell cycle. T-lymphocytes are preferentially inhibited. The T1-helper cell is the main target, although the T1-suppressor cell may also be suppressed. Sandimmune (cyclosporine) also inhibits lymphokine production and release including interleukin-2.
The absorption of cyclosporine from the gastrointestinal tract is incomplete and variable. The extent of absorption is dependent on the individual patient, the patient population, and the formulation. The absolute bioavailability of cyclosproine administered as Sandimmune® is dependent on the patient population, estimated to be less than 10% in liver transplant patients and as great as 89% in some renal transplant patients. Compared to an intravenous infusion, the absolute bioavailability of the oral solution is approximately 30% based upon the results in 2 patients. The cyclosporine capsules and oral solution are bioequivalent. The time of peak blood concentrations (Tmax) following oral administration of cyclosporine [modified] ranged from 1.5 - 2.0 hours.
The steady state volume of distribution during intravenous dosing has been reported as 3 to 5 L/kg in solid organ transplant recipients. Cyclosporine is excreted in human milk.
Hepatic, extensively metabolized by the cytochrome P450 3A enzyme system in the liver. It is also metabolized in the gastrointestinal tract and kidney to a lesser degree. The metabolites are significantly less potent than the parent compound. The major metabolites (M1, M9, and M4N) result from oxidation at the 1-beta, 9-gamma, and 4-N-demethylated positions, respectively.
Elimination is primarily biliary with only 6% of the dose (parent drug and metabolites) excreted in the urine. Only 0.1% of the dose is excreted in the urine as unchanged drug.
Biphasic and variable, approximately 7 hours (range 7 to 19 hours) in children and approximately 19 hours (range 10 to 27 hours) in adults.
Following intravenous administration, the blood clearance of cyclosporine (assay: HPLC) is approximately 5 to 7 mL/min/kg in adult recipients of renal or liver allografts. Blood cyclosporine clearance appears to be slightly slower in cardiac transplant patients. The following are clearance parameters (CL/F) for select patient populations: * 593 ± 204 mL/min [De novo renal transplant patients, 597±174 mg/day] * 492 ± 140 mL/min [Stable renal transplant patients, 344±122 mg/day] * 577 ± 309 mL/min [De novo liver transplant, 458±190 mg/day] * 613 ± 196 mL/min [De novo rheumatoid arthritis, 182±55.6 mg/day] * 723 ± 186 mL/min [De novo psoriasis, 189±69.8 mg/day] * 285 ± 94 mL/min [Stable Liver Transplant, Age 2 - 8, Dosed T.I.D 101±25 mg/day] * 378 ± 80 mL/min [Stable Liver Transplant, Age 8 - 15, Dosed B.I.D 188±55 mg/day] * 171 mL/min [Stable liver transplant, Age 3, Dosed B.I.D 120 mg/day] * 328 ± 121 mL/min [Stable liver transplant, Age 8 - 15, Dosed B.I.D 158±55 mg/day] * 418 ± 143 mL/min [Stable renal transplant, Age 7 - 15, Dosed B.I.D 328±83 mg/day]
The oral LD50 is 2329 mg/kg in mice, 1480 mg/kg in rats, and > 1000 mg/kg in rabbits. The I.V. LD50 is 148 mg/kg in mice, 104 mg/kg in rats, and 46 mg/kg in rabbits.
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