Singapore Drugs Database

Indication

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.

Pharmacokinetics

Absorption

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.

Distribution

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.

Metabolism

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

Clearance

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]

Toxicity

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.

Active Ingredient/Synonyms

Ciclosporin | Ciclosporina | Ciclosporine | Ciclosporinum | CsA | CyA | Cyclosporin | Cyclosporin A | Cyclosporine |