Neoral monitoring by simplified sparse sampling area under the concentration-time curve - Its relationship to acute rejection and cyclosporine nephrotoxicity early after kidney transplantation

Background. Cyclosporine (CsA) dosing is traditionally based on trough bloo d levels (C-0) rather than area under the concentration-time curve (AUC), a lthough AUC correlates better with posttransplantation clinical events. For Neoral, AUC based on limited sampling correlates closely with full 12-hr A UC. The purpose of our study was to correlate C-o with AUC based on CsA lev els at 0, 1, 2, 3, and 4 hr after dose (PK0-4) and to compare this AUC with C-0 in predicting acute rejection (AR) and acute cyclosporine nephrotoxici ty (CsANT) in de novo first kidney transplant patients. Methods. PK0-4, was done 2-4 days after starting Neoral for 156 patients. A ll received CsA-based triple-drug immunosuppression without antibody induct ion. AUC was calculated as projected 12-hr (AUC(0-12)) and actual 4-hr (AUC (0-4)) from the PK0-4 using the parallel trapezoid rule. Neoral dosing was based on C-0 not AUC. AUC was retrospectively compared with C-0 as a predic tor of AR and CsANT during the first 90 days. Results. C-0 correlated poorly with AUC(0-12) and AUC(0-4) (r=0.61 and r=0. 42). C-0 (mean +/- SEM) levels were not significantly different in 34 patie nts with and 109 without AR (293+/-21 vs. 294+/-11 mu g/L, P=0.95). AUC(0-1 2) and AUC(0-4) were significantly lower in pa. tients with than without AR (AUC(0-12) 9090+/-598 vs. 10608+/-336 mu g.h/L, P=0.01; AUC(0-4) 3934+/-30 6 vs. 4802+/-166 mu g.h/L, P=0.006). In stepwise regression analysis only A UC(0-12) AUC(0-4) (P=0.03/P=0.02) and delayed graft function (P=0.007) pred icted AR. AUC(0-12), AUC(0-4), and C-0 were all significantly higher in pat ients with CsANT than without CsANT (AUC(0-12) 11746+/-650 vs. 10023+/-301 mu g.h/L, P=0.01; AUC(0-4) 5270+/-358 vs. 4474+/-150 mu g.h/L, P=0.01; C-0 343+/-18 vs. 287+/-10 mu g/L, P=0.01), but in stepwise regression analysis C-0 was not an independent predictor of CsANT. Patients with AUC(0-12) in t he range of 9500 to 11500 mu g.h/L or AUC(0-4) between 4400 and 5500 mu g.h /L had the lowest incidence of AR (13% and 7%, respectively) without signif icantly higher risk for CsANT. Conclusion. C-0 correlates poorly with AUC based on PK0-4. Early AUC based on PK0.4 is more closely associated with AR and CsANT than is C-0. Our data suggest that a target AUC(0-12) of 9500-11500 or AUC(0-4) of 4400-5500 mu g . h/L may provide optimal Neoral immunosuppression.