Risk Assessment of Drug–Drug Interactions of Calcineurin Inhibitors Affecting Sirolimus Pharmacokinetics in Renal Transplant Patients

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Sirolimus is a mammalian target of rapamycin inhibitor that is being used to prevent organ rejection in kidney transplant patients often in combination with calcineurin inhibitors (CNIs; cyclosporine and tacrolimus). All 3 drugs are metabolized primarily by CYP3As. Clinical drug–drug interaction (DDI) studies of cyclosporine on sirolimus pharmacokinetics have been reported; however, there are a few clinical DDI data related to tacrolimus.


In vitro inhibition assay with sirolimus were conducted using recombinant CYP3As and human microsomes in the presence and absence of CNIs. Sirolimus concentrations were determined by validated high-performance liquid chromatography-tandem mass spectrometry (LC/MS-MS) assay. The DDI risk in terms of increase in sirolimus area under the curve (AUC) was evaluated by a mechanistic model using in vitro inhibition data and published pharmacokinetic parameters of CNIs.


Both CNIs showed similar inhibitory effects on sirolimus metabolism in human liver and intestinal microsomes. Cyclosporine predominantly inhibited CYP3A4 (half maximal inhibitory concentration = 0.71 µM) rather than CYP3A5 (>5 µM), whereas tacrolimus showed similar inhibition for CYP3A4 (0.29 µM) and CYP3A5 (0.41 µM). The predicted increase in AUC of sirolimus during the coadministration of cyclosporine was 3.9-fold, which was comparable to the observed clinical data (3.3-fold) in healthy volunteers. Sirolimus AUC was estimated to a 2.8- to 3.2-fold increase during the coadministration of tacrolimus, based on the reported Cmax values and doses of tacrolimus in kidney transplant patients. In addition, exploratory sensitivity analysis indicated that the predicted increase in sirolimus AUC was sensitive to the free fraction of cyclosporine but not to the free fraction of tacrolimus.


This study suggests that tacrolimus has a lower clinical DDI risk potential affecting sirolimus pharmacokinetics compared with cyclosporine in kidney transplant patients.

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