Calcineurin inhibitors drug interactions

Sirolimus is currently the only FDA-approved ToR inhibitor. One of its derivatives, everolimus, is in phase III clinical trials and has been approved for use in some European countries.30 Sirolimus is a macrolide antibiotic that has no effect on cal-cineurin phosphatase.11,31,32 Sirolimus inhibits T cell activation and proliferation by binding to and inhibiting the activation of the mammalian ToR, which suppresses cellular response to IL-2 and other cytokines (i.e., IL-4 and IL-15J.11,31 Studies have shown that sirolimus may be used safely and effectively with either cyclosporine or tacrolimus as a replacement for either azathioprine or mycophenolate mofetil.33 However, when using both sirolimus and cyclosporine as part of a patient s immunosuppressant therapy, because of a drug interaction between the two resulting in a marked increase in sirolimus concentrations, it is recommended to separate the sirolimus and cyclosporine doses by at least 4 hours. Sirolimus also can be used as an alternative agent for patients who do not tolerate calcineurin inhibitors due to nephrotoxicity or other adverse events.34... 

TABLE 52-6. Potential Drug-Drug Interactions with the Calcineurin Inhibitors and Sirolimus Mediated Through the CYP3A4 Isozyme11... 

Mycophenolate mofetil is available in both oral and intravenous forms. The oral form is rapidly metabolized to mycophenolic acid. Although the cytochrome P450 system is not involved, some drug interactions still occur. Plasma drug levels are frequently monitored, similar to the calcineurin inhibitors and PSIs. 

As most PPIs rely predominantly on fhe CYP2C19 pathway of metabohsm, it is understandable why these drugs are safe in studies examining normal subjects. However, since mutations in the CYP2C19 pathway exist that render the patients "poor metabolizers", a potential interaction between PPIs and calcineurin inhibitors may occur as more PPI metabohsm is shifted to the CYP3A4 enzyme. 

Renal tubular dysfunction is described in animals but human expression in unclear [12]. Most use of mTOR inhibitors is in conjunction with lowered doses of calcineurin inhibitors since it is known that these two drug classes have a potent drug-drug interaction leading to enhanced renal dysfunction compared to the calcineurin inhibitor alone [782]. This may be explained by inhibition of drug efflux pump P-glycoprotein since both siroiimus and the calcineurin inhibitors are competitive substrates [783, 784]. 

Table 3 Drugs that interact with calcineurin inhibitors Decrease concentrations of CNIs...

Sirolimus has been used to spare cyclosporine in the setting of cadaveric renal transplant since unlike the calcineurin inhibitors it is not vasoconstrictive and thus theoretically at least should be of benefit in ischemic reperfusion injury. The studies of Lieberthal mentioned above would lead one to a different strategy. Indeed there are now anecdotes appearing in the literature that similar to experimental animals, sirolimus potentiates ischemic injury following transplantation. There are few data with the combination of sirolimus and tacrolimus. However, limited information suggests that the pattern may be the same. Thus, it is clear that sirolimus used without a calcineurin inhibitor is safe from a nephrotoxic point of view but in combination with a calcineurin inhibitor there are either drug interactions or more fundamental cellular actions of sirolimus that may be adverse to renal tubular cells to impair recovery from ischemic insults such as hypotension and/or acute rejection episodes. 

Therapeutic Uses Mycophenolate mofetil is indicated for prophylaxis of transplant rejection, and it typically is used in combination with glucocorticoids and a calcineurin inhibitor, but not with azathioprine. Combined treatment with siroUmus is possible, although potential drug interactions necessitate careful monitoring of drug levels. For renal transplants, 1 g is administered orally or intravenously (over 2 hours) twice daily (2 g/day). A higher dose, 1.5 g twice daily (3 g/day), is recommended for African American renal transplant patients and all cardiac transplant patients. 

Mori T, Aisa Y, Kato J, Nakamura Y, Ikeda Y, Okamoto S. Drug interaction between oral solution itraconazole and calcineurin inhibitors in allogeneic hematopoietic stem cell transplantation recipients an association with bioavailability of oral solution itraconazole. Int J Hematol 2009 90 103-7. 

The possibility of drug nephrotoxicity has to be excluded, either directly caused by calcineurin inhibitors (ciclosporin, tacrolimus) or more indirectly amplified by drug interactions. Again, the definitive diagnosis is provided by the biopsy, showing acute or chronic lesions associated with calcineurin-in-hibitor-induced nephrotoxicity. 

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