Approaching the Therapeutic Window for Cyclosporine in Kidney Transplantation

Abstract. Neoral dosing is traditionally based on cyclosporine (CyA) trough levels (C 0 ). Four-h area under the curve (AUC 0-4 ) for Neoral in the early posttransplantation period was shown previously to have a better correlation to acute rejection (AR) and CyA nephrotoxicity (CyANT), compared with C 0 . An AUC 0-4 range of 4400 to 5500 μg/h per L during the first week was associated with the lowest AR and CyANT. This article describes a prospective study to assess the feasibility, safety, and efficacy of dosing Neoral solely by AUC 0-4 monitoring, regardless of C 0 , in the first 3 mo after kidney transplantation. Fifty-nine kidney transplant recipients received Neoral-based triple immunosuppression. AUC 0-4 was measured on days 3, 5, 7, 10, and 14 and weeks 3, 4, 6, and 8, then monthly. Target AUC 0-4 was 4400 to 5500 μg/h per L. Dose was adjusted by percentage difference from target AUC 0-4 . Ninety-four percent of AUC were performed on the scheduled day or close to it. No patients had CyANT while AUC 0-4 was in target range. Four patients had reversible CyANT with AUC 0-4 > 5500. Only 1 of 33 patients (3%) who achieved and maintained AUC 0-4 > 4400 by day 3 posttransplantation had AR, whereas 10 of 22 (45%) of those with day 3 to 5 AUC 0-4 < 4400 had AR ( P = 0.0002). In logistic regression analysis, higher early AUC 0-4 was the only significant variable associated with lower serum creatinine at 3 mo. Neoral dose monitoring by AUC 0-4 is a potentially valuable tool for optimizing Neoral immunosuppression. Attainment of a target range of 4400 to 5500 μg/h per L for AUC 0-4 early after transplantation has been demonstrated to reduce significantly the risk of AR and CyANT.