Greater variability of dose-corrected cyclosporine C2 concentrations in renal recipients with acute rejection

FreeText:Immunosuppressive therapy, during the first 3 months in 57 patients given kidney transplants between 1995 and May 2001, consisted of Sandimmun combined with steroid or azathioprine and mycophenolate mofetil. The data for C0, C2 and area under the curve (AUC), as well as their respective dose-corrected concentrations and their respective coefficients of variations (%CV) were compared between recipients with versus without episodes of acute rejection (AR). Therapeutic drug monitoring (TDM) profiles were measured at least three times during the first week, twice during the second week, then weekly during the first month, biweekly during months 2 and 3. Whole blood Sandimmun concentrations were measured with Abbott-TDX kits. The specimens with concentrations higher than 1500 ng/ml were diluted and remeasured. All ARs were confirmed by pathological examination of the biopsy specimen.

Indications:Graft rejection prophylaxis in 57 patients undergoing kidney transplantation

Patients:57 patients.

TypeofStudy:The study aimed to examine the effects of the variability of the dose-corrected Sandimmun concentration C0 (trough level) or C2 (2-hour postdosing concentration) on the occurrence of acute allograft rejection in renal transplant patients during the first 3 months posttransplant.

Results:23 AR episodes during the first 3 months occurred in 19/57 patients (33.3%), whereas the other 38 recipients were rejection-free. The C2 concentrations correlated better with AUC than C0 did (correlation coefficient = 0.81 versus 0.66, respectively; P < .05). The mean %CVs of the dose-corrected C2 concentration among the rejectors (27 ± 2.4%) was significantly higher than that for the nonrejectors (16.6 ± 1.5%, P = .006). The mean %CV of the dose-corrected C0 concentration in rejectors (30 ± 1.6%) was significantly higher than among nonrejectors (22.9 ± 1.9%, P = .012). The mean dose-corrected C2 concentration among the rejectors was significantly lower than that for the nonrejectors (5.2 ± 0.3 versus 7.8 ± 0.5 ng/ml/mg Sandimmun, P = .0001). The mean dose-corrected average concentration (Cav = AUC/dosing interval) in the rejectors was significantly lower than the mean Cav of the nonrejectors (2.4 ± 0.2 versus 3.2 ± 0.2 ng/ml/Sandimmun, P = .013). The mean C2 concentration in the nonrejectors was only slightly but not significantly higher than that of the rejectors (1474.4 ± 53.6 versus 1359 ± 41 ng/ml, P = .09).

AdverseEffects:No adverse events were mentioned.

AuthorsConclusions:This study identified some PK risk factors associated with acute rejection in renal recipients during the early post-transplant months. The patients who experienced ARs had significantly higher degrees of variability in their dose- corrected C2 and C0 concentrations during the first 3 months posttransplant, implying a more unstable PK status. These rejectors also had significantly lower dose-corrected C2 and Cav values, probably due to poorer absorption or faster drug metabolism. But interestingly, we did not find the C2 concentrations in the rejectors to be significantly lower than those in the nonrejectors.

DosageDuration:Dosage and duration not stated.