Cyclosporine A (CsA) is a hydrophobic cyclic undecapeptide, isolated from the fungus Tolypocladium inflatum. The discovery of the drug as a potent immunosuppressant during the 1970s1 opened a new era in immunopharmacology. By reducing morbidity and improving patient and graft survival rates significantly, the drug facilitated routine organ transplantations, which were more experimental in nature at that time.
Mechanism of Action
CsA has been found to inhibit the immune responses mediated by the production and release of T-cells and lymphokines. Cyclosporine binds to the cytosolic proteins of the cyclophilin family, forming the CsA-cytosolic complex, which blocks calcineurin activity, an important enzyme in T-cell activation. This chain of events results in the suppression of the humoral and cell-mediated immunity2.
Cyclosporine, a calcineurin inhibitor, is commonly used for the following indications3:
- Prevention of transplant rejection
- Prophylaxis against host-versus-graft disease
- Psoriasis in non-immunocompromised adults, who have severe recalcitrant plaques
- Severe active rheumatoid arthritis, nonresponsive to methotrexate monotreatment
- Atopic dermatitis
- Nephrotic syndrome
- Ocular inflammation associated with keratoconjunctivitis sicca
- Nephrotoxicity and hepatotoxicity
- Hypertension and increased risk for infections
- Lymphomas and other malignancies, especially of the skin
- Gingival hyperplasia and hypertrichosis
- Hyperkalemia, hyperglycemia, hyperlipidemia and hyperuricemia
- Neurological complications including mild tremor, frank delirium, and seizures
- Gastrointestinal side effects such as nausea, diarrhea, and dyspepsia
The metabolism of cyclosporine involves the cytochrome P-450 system. Alterations in the P-450 system caused either by hepatic dysfunction or due to the concomitant administration of other medications can change CsA levels.
Substances Interfering with Cyclosporine Blood Levels
Substances that increase cyclosporine levels
Substances that decrease cyclosporine levels
Calcium channel blockers: diltiazem, nicardipine, verapamil
Anticonvulsants: carbamazepine, phenobarbital, phenytoin
Antibiotics or antifungals: erythromycin, clarithromycin, doxycycline, fluconazole, itraconazole, ketoconazole
Antibiotics: rifabutin, rifampin, nafcillin
Others: colchicine, cimetidine, tacrolimus, tamoxifen, metoclopramide, grapefruit juice
Others: omeprazole, sulfinpyrazone
Dosage and Administration
The drug is commonly administered orally or intravenously.5 The dosage varies depending on the type of organ transplanted, and also on whether the drug is non-modified (conventional oil-based oral formulation that requires bile for absorption) or modified (depends less on bile for absorption).3
- Renal: 9 ± 3 mg/kg/day, in 2-3 divided doses/day
- Liver: 8 ± 4 mg/kg/day, in 2-3 divided doses/day
- Heart: 7 ± 3 mg/kg/day, in 2-3 divided doses/day
- Single oral induction dose of 15 mg/kg/day (range 14-18 mg/kg)
- The initial oral dose is continued daily for 1-2 weeks and reduced by 5% every week to 5-10 mg/kg/day (maintenance dose)
- Induction dose for IV infusion is a single dose of 5-6 mg/kg/day for 2-6 hours. IV infusion is recommended only in patients who are not able to consume capsules or oral solutions, and should be switched to oral route as soon as possible3
Monitoring Cyclosporine Levels
The narrow therapeutic index and variable absorption and pharmacokinetics of CsA have mandated the need for regular monitoring of its serum concentrations. Circulating CsA level monitoring is important for achieving optimal immunosuppression, with minimal adverse effects, including nephrotoxicity and hepatotoxicity.
The various therapeutic drug monitoring (TDM) strategies employed for monitoring CsA concentration in blood include:
- Trough level concentration (C0) monitoring
- Convenient, simple, practical and routine index for monitoring cyclosporine levels
- Area under the curve (AUC) monitoring7
- More sensitive marker of CsA absorption.
- Studies have found that AUC monitoring in the first 0-4 hours (AUC0-4h) after CsA administration accurately predicts post transplantation clinical events
- C2 monitoring
- Single sampling approach
- Based on the blood concentration at 2 hours post drug administration or by measuring the AUC time curve within the first 4 hours after dosing.8
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- 1 Heuslera K, et al. SWISS MED WKLY. 2001;131:299-302.
- 2 Mascarell L, et al. Mini Rev Med Chem. 2003 May;3:205-14.
- 3 Lance LL, Lacy CF, Goldman MP, Armstrong LL. Quick Look Drug Book. Lippincott Williams & Wilkins; 2007:223.
- 4 Merck. Cyclosporine. Link. Accessed February 2009.
- 5 Franco KL et al. Advanced Therapy in Thoracic Surgery. PMPH-USA; 2005:348.
- 6 Dhillon S, Kostrzewski A. Clinical Pharmacokinetics. Pharmaceutical Press; 2006. 220-224.
- 7 Morris RG. Clin Biochem Rev. 2003 May;24:33-46.
- 8 Burton ME, et al. Applied Pharmacokinetics & Pharmacodynamics: Principles of Therapeutic Drug Monitoring. Lippincott Williams & Wilkins; 2005:521.