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

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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 to 87% over the exposure range without a significant relation to Cmin (P =0.37). The incidence of hypertriglyceridemia, defined as >2.9 mmol/liter, rose from 59 to 77% across the exposure groups (P =0.02). Leukocytopenia, defined as <4×109/liter, occurred in 11–19% of patients across the exposure quintiles showing no relationship to Cmin (P =0.76). The incidence of thrombocytopenia, defined as <100×109/liter, occurred in ≤10% of patients in the first 3 Cmin quintiles and was 14 and 17% in Cmin quintiles 4 and 5 (P =0.21). A significantly increased risk of acute rejection was observed at everolimus trough levels <3 ng/ml. This is a lower therapeutic concentration limit when everolimus is used with conventionally dosed cyclosporine. Because hyperlipidemias responded to counter-measure therapies and thrombocytopenia had an overall low incidence of 12%, everolimus-related adverse events were manageable up to the highest troughs observed in this population of 15 ng/ml. An upper therapeutic concentration limit is likely more than15 ng/ml but a precise value could not be derived from these data.