Optimal dosing and duration of oral everolimus to inhibit in-stent neointimal growth in rabbit iliac arteries

Background: Everolimus is an orally active derivative of sirolimus. Oral administration of rapamycin is efficacious in the reduction of neointima formation and clinical restenosis; however, its optimal dose and duration have not been determined. Methods: New Zealand White rabbits were divided into three groups. The first (low-dose) group received 1.5 mg/kg everolimus 1 day before stenting, followed by 0.75 mg/kg/day everolimus for 28 days. The second (high-dose) group received 6 mg/kg everolimus 1 day before, on the day of, and on the day after stenting, followed by 2 mg/kg/day for 4 days. The third (placebo) group received a matching volume of vehicle similar to that of Group 2. Twenty-eight days after stenting, animals were euthanized and morphometry was performed. Results: In the high-dose group, circulating everolimus levels corresponded with administrated dose levels; by Day 12, no circulating everolimus could be detected. In the low-dose everolimus group, levels remained constant up to 28 days. When compared with placebo, low-dose everolimus was associated with a significant reduction in medial thickness (32%), neointimal area (60%), and percent stent stenosis (33%); however, high-dose everolimus had no significant effect. Conclusions: In conclusion, oral everolimus suppresses in-stent neointimal growth in rabbit iliac arteries. Four weeks of low-dose everolimus is more effective than 7 days of high-dose everolimus. (C) 2006 Elsevier Inc. All rights reserved.