Exposure-response relationships for everolimus in de novo kidney transplantation: defining a therapeutic range

Transplantation
John M KovarikChristiane Rordorf

Abstract

Exposure, safety, and efficacy data from the two everolimus randomized, double-blind phase 3 trials were evaluated to identify a therapeutic concentration range applicable in de novo kidney transplantation. A total of 695 evaluable everolimus-treated patients received either 0.75 or 1.5 mg bid in addition to corticosteroids and cyclosporine (troughs 150-400 ng/ml in month 1 and 100-300 ng/ml thereafter). A total of 3355 everolimus trough levels (Cmin) were obtained in weeks 1 and 2 and months 1, 2, 3, and 6 after transplantation. Each patient's average Cmin was calculated and the values were divided into quintiles: 1.0-3.4, 3.5-4.5, 4.6-5.7, 5.8-7.7, 7.8-15.0 ng/ml (139 patients per quintile). Efficacy was freedom from biopsy-confirmed acute rejection. Safety measures were maximum total cholesterol and triglyceride levels and minimum leukocyte and platelet counts. A sigmoid exposure-response model was used to test the significance of these Cmin-efficacy and Cmin-safety relationships. Freedom from acute rejection was significantly related to Cmin with an incidence of 68% at 1.0-3.4 ng/ml, 81-86% at 3.5-7.7 ng/ml, and 91% at 7.8-15.0 ng/ml (P=0.03). The incidence of hypercholesterolemia, defined as >6.5 mmol/liter, ranged from 76...Continue Reading

References

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