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Cyclosporine (Cs) dosing is traditionally based on trough blood levels (CO). For Neoral, "area under the curve" (AUC) based on Cs levels at 0, 1,2,3 and 4 hours post dose (Pko-4) correlates with AUC based on the less convenient standard 12 hour pharmacokinetics. The purpose of our study was to correlate Co with AUC based on Pko-4, and to compare this AUC with Co in predicting acute rejection (AR) and Cs nephrotoxicitv (CsNT) after first kidney transplants. Methods: Pko-4 was done 2-4 days after initiation of Neoral for 100 kidney transplant recipients. All received induction with continuous i.v. Cs for 1-3 days, without antibody. AUC was calculated from the Pko-4 using the parallel trapezoid rule. Neoral dosing was based on CO, not AUC. AUC was retrospectively compared to Co as a predictor of AR and CsNT during the first 90 days. Results: Co correlated poorly with AUC (r2 = 0.343). Co (mean +_ SEM) levels were not significantly different in 25 patients (pts) with and 75 without AR (267+_28 vs 293+_12 mcg/L, p= 0.397). AUC was significantly lower in pts with than without AR (8628+_722 vs 10502+_396 mcg/L.h, p= 0.021). In pts with AR in the first 15 days (19/25 pts), mean AUC was even more significantly lower than in pts without AR (7919+_724 vs 10385+_389 mcg/L.h, p= 0.004). In logistic regression analysis only AUC (n= 0.007) and delayed graft function (n= 0.0006) but not HLA mismatch, source of transplant, PRX, type of immunosuppresion or Co predicted AR. AUC and Co were both significantly higher in pts with CsNT than without CsNT(12418+_977 vs 9316+374mcg/L.h, p=0.0005; 336+_22 vs 276+_14 mcg/L, p= 0.042), but AUC relation to CsNT was more significant. Pts with AUC in the range of 9500-11500 mcg/L.h had the lowest incidence of AR (8%, p< 0.05), without significantly higher risk for CsNT. Conclusion: CO correlates poorly with AUC based on Pko-4. Early AUC based on Pko-4 is more closely associated with AR and CsNT than is Co. Our data suggest a target AUC of 9500- 11500 mcg/L.h may provide optimal Neoral immunosuppression. AUC determination for Neoral is now relatively simple and convenient, and may be a more effective marker than Co for dosing in the early post-transplant period.