Everolimus in de novo cardiac transplantation: Pharmacokinetics, therapeutic range, and influence on cyclosporine exposure

Background: We evaluated exposure, safety, and efficacy data from an international Phase 3 trial of everolimus in de novo heart transplantation to characterize the longitudinal pharmacokinetics of everolimus and cyclosporine and to identify a therapeutic concentration range for everolimus. Methods: We randomized 634 patients to receive either 0.75 mg everolimus twice daily, 1.5 mg everolimus twice daily, or azathioprine in addition to corticosteroids and cyclosporine. At 8 visits during the first 6 months after transplantation, we obtained 2,328 everolimus trough levels (Cmin) and 129 area-under-the-curve (AUC) profiles over the dosing interval in patients treated with everolimus; we collected 3,258 cyclosporine trough concentrations and 174 profiles in all 3 treatment arms. We used median-effect analysis to characterize exposure-response associations between everolimus average Cmin vs freedom from biopsy-confirmed acute rejection; maximum cholesterol, low density lipoprotein, triglyceride, and creatinine levels; and minimum leukocyte and platelet counts. Results: Everolimus Cmins averaged 5.2 ± 3.8 ng/ml and 9.4 ± 6.3 ng/ml at the lower and upper dose levels. A 17% underproportionality was noted in Cmins; however, peak exposure and AUC were consistent with dose proportionality. Everolimus exposure was stable during the 6-month period. Interindividual variability was 37% for AUC and 40% for Cmin. The latter parameter was not influenced to a clinically relevant extent by sex, age, or weight. The Cmin was well correlated with AUC (r2 = 0.81). Everolimus Cmin was significantly related to freedom from rejection (p = 0.02) with 3 ng/ml being an informative lower threshold for efficacy. Thrombocytopenia, defined as <75 × 10⁹/liter, was related significantly to Cmin (p = 0.03); however, the incidence in this study was too low to establish an upper end for the therapeutic range. Lower doses of cyclosporine (by 15% to 19%) were used in patients treated with everolimus to achieve cyclosporine Cmins and AUCs similar to those in patients treated with azathioprine. Conclusions: Everolimus exposure was dose proportional and stable during the first 6 months after transplantation. Interindividual pharmacokinetic variability was high but not influenced by common demographic covariates. We observed a significantly increased risk of acute rejection at everolimus trough levels <3 ng/ml, which constitutes the lower therapeutic concentration limit when everolimus is used with conventionally dosed cyclosporine. Everolimus-related adverse events were manageable up to the highest troughs (22 ng/ml) observed in this population. We could not derive a precise upper therapeutic concentration limit from these data.