Background: 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.
Methods: 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.
Results: 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 microg.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 microg.hr/L on day 3 to 2316+/-697 microg.hr/L on day 14 (P=0.067). Mean AUC[0-4] was 4566+/-1463 microg.hr/L by day 3 and also did not change significantly, although the dose-adjusted AUC[0-4] rose by 31% from 952+/-317 microg.hr/L on day 3 to 1250+/-697 microg.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<0.005) and a significant decrease in coefficient of variation for AUC[0-12] (35% vs. 21%, P<0.005) and for Tmax (47.4% vs. 33.1%, P<0.005). Predosage trough level (C0) was a poor predictor of drug exposure, with R2 values less than 0.5 for AUC[0-4] and 0.7 for AUC[0-12] at all time points. Sparse sample modeling identified three 3-point sparse-sampling strategies that predicted AUC[0-12] and AUC[0-4] with R2 values approaching or exceeding 0.9 on all three study days; C2 or C3 seemed to be the most important single predictor, with R2 values > 0.80. Ten of the 36 treated patients (27.8%) experienced 13 episodes of acute rejection by 28 days posttransplant. Longitudinal logistic regression showed no association between C0 and rejection, but lower AUC[0-12] values were marginally (P=0.099) and lower AUC[0-4] values were significantly (P=0.046) associated with increased risk of rejection. CsA exposure on day 7 (n=29) was significantly lower in patients who experienced acute rejection in the second week than in those who were rejection free whether measured by AUC[0-12] (7976+/-1476 vs. 10,239+/-2759 microg.hr/L; P=0.048), AUC[0-4] (4027+/-412 vs. 5623+/-1389 microg.hr/L; P<0.0001), C2 (1116+/-183 vs. 1852+/-522 microg/L; P<0.0001), or Cmax (1415+/-323 vs. 2084+/-450 microg/L; P=0.005), and rejection was significantly less common in patients with an AUC[0-4]> 4,500 microg.hr/L (7% vs. 40%; P=0.041) or a C2 level>1500 microg/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.
Conclusions: 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 microg.hr/L or C2 1500 microg/L are desirable to minimize the risk of rejection.