ABSORPTION PROFILING OF CYCLOSPORINE MICROEMULSION (NEORAL) DURING THE FIRST 2 WEEKS AFTER RENAL TRANSPLANTATION1

Abstract

Evidence suggests that optimal immunosuppressive drug exposure must be achieved early posttransplant to minimize the risk of acute graft rejection. This study was designed to examine the absorption profile of Neoral during the first 2 weeks after renal transplantation, to develop simple sparse-sampling pharmacokinetic methods to predict exposure, and to explore the target range for optimal clinical immunosuppression under conditions of normal clinical practice. The prospective multicenter study was conducted in six Canadian renal transplant centers in patients receiving Neoral-based immunosuppression. Full (8-point) pharmacokinetic studies were performed on days 3, 7, and 14 posttransplant in a nested subset of patients, and the occurrence and severity of acute rejection, infection or other adverse effects, routine laboratory parameters, and vital signs were assessed on days 3, 7, 14, and 28. A total of 38 adult kidney graft recipients were studied, of whom a nested subset of 16 patients had complete 12-hr pharmacokinetic (PK) data on all 3 sampling days. Mean area under the time-concentration curve over the entire 12-hr dosage interval (AUC[0–12]) was 9249±3236 μg·hr/L by day 3 and did not change significantly throughout the study, although dose-corrected AUC[0–12] rose by 20% from 1924±671 μg·hr/L on day 3 to 2316±697 μg·hr/L on day 14 (P =0.067). Mean AUC[0–4] was 4566±1463 μg·hr/L by day 3 and also did not change significantly, although the dose-adjusted AUC[0–4] rose by 31% from 952±317 μg·hr/L on day 3 to 1250±697 μg·hr/L on day 14 (P =0.009). AUC[0–4] represented 52% of the AUC[0–12] values across the three PK study days and closely predicted this latter value (R2=0.803 day 3, R2=0.972 day 14). Cyclosporine (CsA) concentration profiles became more uniform throughout the first 14 days posttransplant, with a reduction in Tmax from 2.45 to 1.48 hr (P 1500 μg/L (0% vs. 58%;P <0.001) on day 7 (sensitivity, 100%; specificity, 75%; positive predictive value, 58%; negative predictive value, 100%). There was no evident relationship between CsA exposure and renal toxicity within this patient sample. Absorption of CsA is highly heterogeneous immediately posttransplant, although the pharmacokinetic profile normalizes, interpatient variability decreases, and CsA absorption increases throughout the first 2 weeks permitting a reduction in Neoral dose to achieve constant exposure. Trough (C0) levels do not accurately predict CsA exposure or rejection risk and should be replaced by sparse or single point (C2) sampling methods, which offer a high predictive value to optimize the use of this drug and reduce rejection risk. Acute rejection is significantly more common with low CsA exposure during the first week posttransplant, and levels above the threshold of approximately AUC[0–4] 4500 μg·hr/L or C2 1500 μg/L are desirable to minimize the risk of rejection.