Adequate Early Cyclosporin Exposure is Critical to Prevent Renal Allograft Rejection: Patients Monitored by Absorption Profiling

Abstract

This study used receiver operating characteristic analysis to investigate the properties of area under the concentration‐time curve during the first 4 h after cyclosporin‐microemulsion dosing (AUC0−4) and cyclosporin (CyA) levels immediately before and at 2 and 3 h after dosing (C0, C2 and C3) to predict the risk of biopsy‐proven acute rejection (AR) at 6 months. Ninety‐eight kidney transplant recipients treated with CyA‐microemulsion‐based triple therapy immunosuppression were studied on post‐transplant days 3, 5, and 7, and at increasing intervals thereafter.The most sensitive and specific predictor of AR was AUC0−4. Of the single time‐point measurements, the measurement properties of C2 were closest to those of AUC0−4, and superior to those of C3. The relationship between C0 and subsequent AR was weak and did not reach statistical significance. On day 3, CyA AUC0−4≥ 4400 ng . h/mL and C2≥ 1700 ng/mL were each associated with a 92% negative predictive value for rejection in the first 6 months. Pharmacokinetic measurements on or after day 5, and measurements on day 3 in patients with delayed graft function, were not predictive of AR.Adequate exposure within the first 3 days post transplantation may be critically important in preventing subsequent rejection. This study used receiver operating characteristic analysis to investigate the properties of area under the concentration‐time curve during the first 4 h after cyclosporin‐microemulsion dosing (AUC0−4) and cyclosporin (CyA) levels immediately before and at 2 and 3 h after dosing (C0, C2 and C3) to predict the risk of biopsy‐proven acute rejection (AR) at 6 months. Ninety‐eight kidney transplant recipients treated with CyA‐microemulsion‐based triple therapy immunosuppression were studied on post‐transplant days 3, 5, and 7, and at increasing intervals thereafter. The most sensitive and specific predictor of AR was AUC0−4. Of the single time‐point measurements, the measurement properties of C2 were closest to those of AUC0−4, and superior to those of C3. The relationship between C0 and subsequent AR was weak and did not reach statistical significance. On day 3, CyA AUC0−4≥ 4400 ng . h/mL and C2≥ 1700 ng/mL were each associated with a 92% negative predictive value for rejection in the first 6 months. Pharmacokinetic measurements on or after day 5, and measurements on day 3 in patients with delayed graft function, were not predictive of AR. Adequate exposure within the first 3 days post transplantation may be critically important in preventing subsequent rejection.