Pharmacokinetic and Pharmacodynamic Assessments of HMG‐CoA Reductase Inhibitors When Coadministered with Everolimus

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Abstract
The authors assessed the mutual influence of the immunosuppressant everolimus (Certican) and the HMG‐CoA reductase inhibitors atorvastatin and pravastatin when coadministered based on pharmacokinetic and pharmacodynamic measures. In this randomized, open‐label, three‐way crossover study, 24 healthy men received three single‐dose oral treatments: 2 mg everolimus, 20 mg atorvastatin (n = 12) or 20 mg pravastatin (n = 12), and the respective statin coadministered with everolimus. Consecutive treatments were separated by a 14‐day washout. The pharmacokinetics of all three drugs and total HMG‐CoA reductase inhibitors were measured. Everolimus Cmax was reduced by 9% and 10% with atorvastatin and pravastatin coadministration; the corresponding decreases in everolimus AUC were 5% and 6%, respectively. Everolimus coadministration increased the Cmax of atorvastatin by 11% but had no influence on atorvastatin AUC. Coadministration of everolimus with pravastatin was associated with a 10% decrease in pravastatin Cmax and a 5% decrease in the AUC. The elimination half‐lives of the two statins were unaffected by everolimus. Changes in total HMG‐CoA reductase inhibitors in plasma exhibited generally similar patterns as for the parent statin exposures. Single‐dose administrations of everolimus with either atorvastatin or pravastatin did not influence the pharmacokinetics of everolimus, atorvastatin, pravastatin, or total HMG‐CoA reductase inhibitors in plasma to a clinically relevant extent.

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