Everolimus in pulmonary transplantation: pharmacokinetics and exposure-response relationships

In this study we evaluated exposure, safety and efficacy data from an international trial of everolimus. We sought to identify a tolerated and efficacious range for blood levels of this agent in maintenance lung transplant recipients.

In a randomized, double-blind, multicenter trial, 213 maintenance lung transplant recipients received either everolimus 1.5 mg twice daily (n = 101) or azathioprine 1 to 3 mg/kg/day (n = 112) with cyclosporine and corticosteroids. At 15 visits over the first 2 years of the trial, we obtained 826 everolimus trough (C0) blood samples. We used median-effect analysis to assess relationships between everolimus C0 vs efficacy and safety responses.

Everolimus administration began at 1.5 mg twice daily and was progressively lowered over the first 2 months to an average of 1.2 +/- 0.4 mg twice daily, which was maintained thereafter. This dose yielded median C0 levels of 6.6 ng/ml (10th to 90th percentiles: 2.8 to 11.8 ng/ml). Over this range of everolimus C0, freedom from a decline in pulmonary function with bronchiolitis obliterans syndrome and freedom from biopsy-proven acute rejection were both > or = 88%. The incidence of increased cholesterol (> 6.5 mmol/liter), increased triglycerides (> 2.9 mmol/liter) and transiently decreased platelet count (< 100 x 10(9)/liter) rose significantly with increasing C0. Infections and drug-related adverse events were not significantly related to exposure.

A tolerated and efficacious concentration range for everolimus in maintenance lung transplantation appears to be 3 to 12 ng/ml when used in conjunction with cyclosporine and corticosteroids. This range should be prospectively assessed with possible refinement as more clinical experience is gained.