Clinical Pharmacokinetics of Cyclosporin

Abstract

Cyclosporin (cyclosporin A) is a unique immunosuppressant used to prevent the rejection of transplanted organs and to treat diseases of autoimmune origin. Therapeutic drug monitoring of cyclosporin is essential for several reasons: (a) wide variability in cyclosporin pharmacokinetics has been observed after the oral or intravenous administration of the drug. The variability in the kinetics of cyclosporin is related to a patient’s disease state, the type of organ transplant, the age of the patient and therapy with other drugs that interact with cyclosporin; (b) maintaining a blood concentration of cyclosporin required to prevent rejection of the transplanted organ; (c) minimising drug toxicity by maintaining trough concentrations below that which toxicity is most likely to occur; and (d) monitoring for compliance since patient non-compliance with drug regimens is a significant reason for graft loss after 60 days. Clinical monitoring and pharmacokinetic studies of cyclosporin can be performed using different biological fluids (plasma, serum or whole blood) and different analytical techniques (radioimmunoassay or high pressure liquid chromatography). The available analytical methods provide different results when using blood, plasma, or serum. Comparison of therapeutic ranges and pharmacokinetic parameters should be made with careful attention given to the method of cyclosporin analysis. Following oral administration, the absorption of cyclosporin is slow and incomplete. Peak concentrations in blood or plasma are reached in 1 to 8 hours after dosing. The bioavailability of cyclosporin ranges from less than 5% to 89% in transplant patients; poor absorption has frequently been observed in liver and kidney transplant patients and in bone marrow recipients. Factors that affect the oral absorption of cyclosporin include the elapsed time after surgery, the dose administered, gastrointestinal dysfunction, external bile drainage, liver disease, and food. Cyclosporin is widely distributed throughout the body. Following intravenous administration, the drug exhibits multicompartmental behaviour. The volume of distribution (whole blood; HPLC) ranges from 0.9 to 4.8 L/kg. Cyclosporin is highly bound to erythrocytes and plasma proteins and has a blood to plasma ratio of approximately 2. In plasma, approximately 80% of the drug is bound to lipoproteins. The distribution of cyclosporin in blood can be affected by a patient’s haematocrit and lipoprotein profile. Cyclosporin is extensively metabolised, primarily by mono- and dihydroxylation as well as N-demethylation, and is considered a low-to-intermediate clearance drug. The clearance of cyclosporin (whole blood; HPLC) ranges from 2.0 ml/min/kg in children with congestive heart failure to 11.8 ml/min/kg in paediatric kidney transplant patients. The terminal elimination half-life is highly variable and ranges from 6.3 hours in healthy volunteers to 20.4 hours in patients with severe liver disease (blood; H PLC). Factors affecting the metabolism of cyclosporin include liver disease, age, and concurrent drug therapy. The major route of elimination of cyclosporin is via the bile, primarily as metabolites of the drug. Renal excretion is a minor elimination pathway. Renal failure and haemodialysis do not alter the pharmacokinetics of cyclosporin. Several drugs are known to interact with cyclosporin, including microsomal enzyme inducing and inhibiting agents. Several drugs including amphotericin B, aminoglycoside antibiotics and co-irimoxazole may potentiate the nephrotoxicity of cyclosporin. The dose of cyclosporin used in a patient should be adjusted after considering factors such as the initial response to therapy, the patient’s age, transplant type, disease state and concurrent drug therapy. Initial doses are usually in the range of 10 to 20 mg/kg/day orally or 2.5 to 5 mg/kg/day as an intravenous infusion, and should be adjusted based on the clinical status of the patient and cyclosporin blood concentrations. Long term oral maintenance doses of less than 3 mg/kg/day have resulted in adequate immunosuppression in some patients. The therapeutic range for cyclosporin is poorly defined and depends on the biological fluid being analysed, the analytical technique and the time after transplant. Cyclosporin concentration monitoring should be used in conjunction with other assessment criteria such as serum biochemical parameters, radiological studies, biopsy results and the clinical status of the patient. Even though our understanding of cyclosporin is incomplete, a thorough knowledge of different factors that affect its kinetics will aid the clinician in optimising immunosuppression with this promising new agent.