Clinically Significant Drug Interactions with Cyclosporin

Abstract

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.

Effect of acute and chronic treatment of Cyclosporin A on liver and kidney functions in rats

“…liver and excreted mainly into the bile. The therapeutic drug monitoring of CsA is essential to optimize the immunosuppressant therapy due to large inter-and intra-individual variability in the pharmacokinetics of this drug (Campana et al, 1996).…”

Effect of cyclophosphamide on serum cyclosporine levels at the conditioning of hematopoietic stem cell transplantation

“…Drugs that have interactions with CsA are generally metabolized by hepatic P-450, and this overlapping metabolic pathway is considered the main mechanism of drug effects on CsA levels. 5,6,38 Physical attributes, such as gender and age, have also been reported related to the serum CsA concentrations. 39,40 As younger people have a more rapid CL and a larger Vss than the elderly, caution with serum CsA doses based on differences in age has been claimed to be required.…”

“…1,2 The administration of CsA can be difficult, because it has a narrow therapeutic range and because its serum level can be affected pharmacologically by many substances, such as fluconazole, macrolide antibiotics, and calcium channel blockers. [4][5][6] An increased serum CsA concentration may induce nephrotoxicity and neurotoxicity; decreased concentrations may cause severe acute GVHD. [1][2][3][5][6][7][8] CsA is metabolized primarily by cytochrome P-450 enzymes, which exist in the endoplasmic reticulum, especially high concentrations in hepatocytes and the enterocytes of the intestine.…”

“…[4][5][6] An increased serum CsA concentration may induce nephrotoxicity and neurotoxicity; decreased concentrations may cause severe acute GVHD. [1][2][3][5][6][7][8] CsA is metabolized primarily by cytochrome P-450 enzymes, which exist in the endoplasmic reticulum, especially high concentrations in hepatocytes and the enterocytes of the intestine. 4 In P-450 enzymes, P-450 3A4 predominantly metabolizes CsA, and this enzyme family is subjected to both induction and inhibition by several agents.…”

Tacrolimus: a new agent for the prevention of graft-versus-host disease in hematopoietic stem cell transplantation

“…Drug interactions with tacrolimus that are known to occur or for which a strong possibility for interaction exists are listed in Table 3. Agents known to induce or inhibit the P450 enzyme system should be administered with caution to patients receiving tacrol- Table 3 Potential drug interactions with tacrolimus 27,30,115,116,[120][121][122][123][124][125][126][127][128][129] imus, and close therapeutic drug monitoring should be performed. Pharmacokinetic studies in BMT patients who received tacrolimus alone or in combination with methylprednisolone or methotrexate showed no difference in clearance of tacrolimus.…”