Efikasnost terapijskog monitoringa ciklosporina odredjivanjem C2 i PIK0−4 tokom prva 24 meseca posle transplantacije bubrega
Authors: Vavic Neven , Ignjatovic Ljiljana , Draskovic Biljana , Hrvacevic Rajko , Kovacevic Zoran , Paunic Zoran 
Published: December 2010

Background/Aim. Cyclosporine (CyA) therapeutic drug monitoring (TDM) through the measurement of drug concentration in blood two hours after the administration (C2), and/or according to the calculated value of the area under the concentration - time curve during the first four hours following administration (AUC0?4) shows favourable correlation with clinical manifestations in patients with kidney transplantation (Tx). The aim of this study was to analyze clinical efficiency and usability of TDM CyA through C2 and AUC0-4 in the group of our kidney transplanted patients during the first 24 months following Tx. Methods. The study included 50 patients who had undergone kidney Tx using living donors at the Clinic of Nephrology Military Medical Academy, from 1996 to 2003. The first group (group C2) consisted of 25 patients in whom CyA dose was adjusted according to the target C2 and AUC0?4 (calculated by the regression formula based on C1, C2 and C3), while the second group (group C0) consisted of 25 "historical" patients in whom the dose of this drug was adjusted according to C0. Results. On the 6th day the average daily dose of CyA in the group C2 was 10.1?0.8 mg/kg, while in the group C0 it was 7.6?1.6 (p < 0.05). One month following the Tx, daily drug doses were quite similar in the two observed groups (6.2 mg/kg in C0 and 6.6 mg/kg in group C2, p = NS). In the group C2, target C2/AUC 0?4 (C2 1 700 ng/ml, AUC0?4 4 400 ng?h/ml) on the sixth day was achieved in 36.3%, and on day 14 in 76% of the patients. The target AUC 0?4, in relation with C2, in each observed time interval was reached in the higher number of patients. Maximum CyA concentrations in the group C2 were registered 2 hours following the administration (C2), when compared with the concentrations registered after the first and the third hour (C1 and C3). In relation with C1 and C3, C2 concentration correlated most favorably with AUC 0?4, both on the 6th (r = 0.85) and on the 9th day (r = 0.87). During the first three months following the Tx, in the group C0, 10 episodes (40%) of acute cell rejection (AR) were registered, while in the group C2, two episodes (8%, p = 0.07) were registered; in the observed period covering the first two years, a total of 13 (52%) AR episodes in the group C0 and 5 AR episodes (20%) in the group C2 (p = 0.03) were registered. All of five episodes of steroid resistant AR were registered in the group C0. In the group C2, all five patients with AR had lower C2 during AR: the average C2 at the moment of AR was 933.8 ng/ml, and in the patients without rejections was 1 364.2 ng/ml (p = 0.008). In the same group, the average C0 at the moment of AR was 263.2 ng/ml, and 240.0 ng/ml (p = 0,486) in the patients without AR. In the C0 group, average C0 concentration at the moment of AR was 227.1 ng/ml, while in the patients without AR it was 227.7 ng/ml (p = 0.95). Totally 68% of the patients showed signs of acute CyA nephrotoxicity during the first year in the group C2, and 52% in the group C0 (p = 0.38). In seven patients (28%) of the group C2 and six patients of the group C0 (24%, p = 0.96) in the first two years following Tx, administration of CyA was interrupted due to nephrotoxicity. Overall graft function was good in both groups during the period of two years. One graft was lost in the group C0 due to chronic allograft nephropathy. The patients in the group C2 had better early and the same late graft function. Five patients in the group C2 who did not reach the target C2/AUC during the first 30 days, did not have more AR or worse graft function, comparing with the patients who reached the target concentrations. Conclusion. In the patients with CyA TDM through with the C2 and AUC0?4., AR frequency was considerably lower, and AR episodes had a milder flow than in those with CyA TDM through the C0. The drug concetration in blood two hours after administration (C2) was a good predictor of acute graft rejection, while C0 failed to point to the patients with the insufficient drug concentration. Higher drug doses were administered in the group C2 during the first month following Tx, and these patients did not show significantly higher frequency of acute nephrotoxicity and more frequent requirement of the drug use interruption. Graft function in both groups was good during the period of two years. CyA dose determination through C2 and AUC0-4 is efficient TDM method, relatively simple for use in day to day clinical practice.