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.

Clinical Pharmacokinetics of Cyclosporin

Cyclosporin is a powerful immunosuppressive drug used in transplantation medicine and to treat autoimmune diseases. It is a lipophilic molecule, with its bioavailability dependent on food, bile and other interacting factors. Cyclosporin is extensively metabolised in the liver by the cytochrome P450 3A system, which is subject to considerable interindividual variation.

Cyclosporin clinical pharmacokinetics

Since its approval in 1983 for immunosuppressive therapy in patients undergoing organ and bone marrow transplants, cyclosporin has had a major impact on organ transplantation. It has significantly improved 1-year and 2-year graft survival rates, and decreased morbidity in kidney, liver, heart, heart-lung and pancreas transplantation. Several studies have supported the efficacy of cyclosporin in preventing graft-versus-host disease in bone marrow transplantation. Cyclosporin is also possibly effective in treating diseases of autoimmune origin and as an antineoplastic agent. The introduction of therapeutic drug monitoring of cyclosporin was extremely useful because of the wide inter- and intraindividual variability in the pharmacokinetics of cyclosporin after oral or intravenous administration. Optimal long term use of cyclosporin requires careful monitoring of the blood (or plasma) concentrations. Sustained and clinically significant drug-drug interactions can occur during long term therapy with cyclosporin. The coadministration of multiple drugs with cyclosporin could result in graft rejection, renal dysfunction or other undesirable effects. Any interaction that leads to modified cyclosporin concentrations is of potential clinical importance. Cyclosporin itself may have significant effects on the pharmacokinetics and/or pharmacodynamics of coadministered drugs, such as digoxin, HMG-CoA reductase inhibitors and antineoplastic drugs affected by multidrug resistance. Many drugs have been shown to affect the pharmacokinetics and/or pharmacodynamics of cyclosporin. Interactions between cyclosporin and danazol, diltiazem, erythromycin, fluconazole, itraconazole, ketoconazole, metoclopramide, nicardipine, verapamil, carbamazepine, phenobarbital (phenobarbitone), phenytoin, rifampicin (rifampin) and cotrimoxazole (trimethoprim/sulfamethoxazole) are well documented in a large number of patients. Other interactions (such as those with aciclovir, estradiol and imipenem) are documented only in isolated case studies.

Clinically Significant Drug Interactions with Cyclosporin An Update

This article reviews the reported pharmacokinetic interactions between cyclosporin and other drugs. Both rifampicin and the majority of anticonvulsants can decrease cyclosporin concentrations to levels that are at or below the limit of detection for most assays. There have been no reports of any interaction between valproic acid and cyclosporin. Other drugs that have been reported to decrease cyclosporin concentration include sulfadimidine and trimethoprim, nafcillin and octreotide. Erythromycin, ketoconazole and some calcium channel blockers have been clearly shown to increase the concentration of cyclosporin. Other less well documented interactions have been reported with other macrolide antibiotics, other azole antifungal drugs, high dose methylprednisolone, metoclopramide, fluoroquinolones, imipenem/cilastatin, oral contraceptives/danazol, sulindac, methyltestosterone, colchicine, acetazolamide, alcohol and cimetidine. Although the most commonly reported mechanism is inhibition of cyclosporin metabolism, there is increasing evidence that erythromycin, metoclopramide and probably other drugs increase the bioavailability of oral cyclosporin. Two calcium channel blockers which have not been reported to interact with cyclosporin are nifedipine and nitrendipine. With increasing use of cyclosporin, the number of drugs reported to interact will rise. Prudent clinicians should monitor the concentration of this agent more frequently when another drug is added or discontinued and cyclosporin dosage should be adjusted when appropriate. Sustained changes in cyclosporin concentration can result in graft rejection (or graft-versus-host disease) or renal toxicity. Further studies are needed to determine the mechanism of most of these interactions.

Pharmacokinetic Drug Interactions with Cyclosporin (Part II)

1 An emulsion preparation of cyclosporin was administered locally to different parts of the small and large intestine by gavage: to the duodenum (opposite to the papilla of Vater), jejunum (150 cm distal to the teeth), ileum (300 cm distal to the teeth), and to the colon descendens (30 cm proximal to the anus) 2 The bioavailability of cyclosporin after these instillations was compared with that after oral administration of a hard gelatine capsule formulation 3 Cyclosporin was found to be absorbed predominantly in the small intestine This may have implications for dosage in patients with reduced absorptive surface area

https://bpspubs.onlinelibrary.wiley.com/doi/pdf/10.1111/j.1365-2125.1992.tb03998.x

The absorption site of cyclosporin in the human gastrointestinal tract.

Cyclosporin A (CyA) is a powerful immunosuppressive agent whose lack of myelotoxicity makes it unique among nonsteroidal drugs currently given for immunosuppression. It has been used with initial success in recipients of kidney, liver, bone marrow and pancreas transplants, and it may also have clinical application in the treatment of autoimmune disorders. In regard to its use in transplant recipients, there are many remaining questions about its mechanism of action, the optimum dose, whether it should be used alone or with other immunosuppressants, whether it can suppress chronic rejection and what its long-term side effects may be. These questions can only be answered by further careful laboratory investigation and controlled clinical trials. Until then, CyA should only be administered in centres experienced in its use.

Cyclosporin A: a powerful immunosuppressant

The effects and side effects of cyclosporine: relationship to drug pharmacokinetics.

Organ transplantation has become the treatment of choice for selected patients with end-stage failure of the heart, liver or kidneys. The expanding role for organ transplantation, however, has led to a corresponding increase in the complexity of patient management. In response to these changes, University Hospital, London, Ont., has established an interdisciplinary multi-organ transplant service (MOTS). MOTS coordinates donor organ procurement and patient management. Donor organs have been retrieved from as far south as Dalton, Georgia, as far west as Calgary and as far east as Halifax. As of Dec. 31, 1985, 485 transplants had been performed, including 387 kidney transplants, 51 heart transplants, 3 heart/lung transplants, 43 liver transplants (in adults and children) and 1 pancreas transplant. With current immunosuppressive protocols MOTS projects 1-year patient survival rates of 95% after kidney transplantation, 88% after heart transplantation and 81% after liver transplantation. Patient rehabilitation has been excellent.

Experience of a Canadian multi-organ transplant service.

The side effects of cyclosporin A: clinical and histologic findings following 31 canine heterotopic cardiac allotransplants.

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Cyclosporin A: a powerful immunosuppressant

The effects and side effects of cyclosporine: relationship to drug pharmacokinetics.

Experience of a Canadian multi-organ transplant service.

The side effects of cyclosporin A: clinical and histologic findings following 31 canine heterotopic cardiac allotransplants.