Everolimus in pulmonary transplantation: Pharmacokinetics and exposure-response relationships

Background: 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. Methods: 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. Results: 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 <88%. The incidence of increased cholesterol (>6.5 mmol/liter), increased triglycerides (>2.9 mmol/liter) and transiently decreased platelet count (<100 × 10⁹/liter) rose significantly with increasing C₀. Infections and drug-related adverse events were not significantly related to exposure. Conclusions: 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.