Jolanta Kamińska, Maciej Głyda, Joanna Sobiak, Maria Chrzanowska calculated as a result of subtraction of MPA molar concentration before the hydrolysis from MPA con- centration after the enzymatic hydrolysis (CMPAG = CMPA after enzymatic hydrolysis – CMPA before hydrolysis). The MPAG was generously supplied by Roche Pharma- ceuticals (Palo Alto, CA). The analysis method had a linear range of 0.1-25.0 μg/ml and 10-250 μg/ml for MPA and MPAG, respectively. Accuracy of MPA and MPAG batches ranged from 97.4% to 106.4% and from 96.5% to 116.6%, respectively, and the precision, expressed as the percentage of coefficient of vari- ation (% CV), ranged from 0.8% to 6.9% and from 0.9% to 17.4%, respectively. The following PK parameters for MPA and MPAG were calculated: pre-dose concentration (C0), maximum concentration (Cmax) and area under the plasma concentration – time curve from 0 to 4 h (AUC0-4 h) using the linear trapezoidal rule. Inter- patient variability was assessed as % CV. Ccr was estimated using the Cockcroft-Gault formula. All statistical tests were performed using Sta- tistica software version 8.0 and p value < 0.05 was considered significant. Chi-square test was used for the evaluation of qualitative data. Nor- mality was determined by Shapiro-Wilk W test. Data were evaluated by the Mann-Whitney test and Spearman correlation analysis. Multivariate analysis was performed to evaluate the influence of various clinical determinants on MPA and MPAG PK parameters. For multivariate analysis both PK parameters corrected and uncorrected for MMF dose were examined. In the remaining analyses only dose-corrected values were con- sidered. The study was performed following the recom- mendations of the Declaration of Helsinki and approved by the Bioethical Commission at the Poz- University of Medical Sciences. Informed con- sent was obtained from all patients prior to initi- ating the study. A 18 PdAM l] 1164 e z / m lia [gμ12 rm n10 on itao 8 i-seaoddn rtcceonn 642 e M 0 90 Results The two groups of patients (with Ccr above or below 60 ml/min) were comparable for sex, age, time elapsed after renal transplantation, body weight, MMF dose and for number of patients receiving CsA or Tac. For groups with normal and impaired renal function, medians of serum creati- nine were 1.3 mg/dl and 2.1 mg/dl, respectively, and median Ccr 75.2 ml/min and 44.9 ml/min, respec- tively. The MPA C0 values were significantly higher in patients with impaired renal function than in patients with normal renal function. However, AUC0-4 h and Cmax values were not significantly dif- ferent between the two groups (Figure 1, Table II). Moreover, the values of PK parameters for MPAG (AUC0-4 h, C0 and Cmax) were also significantly higher in patients with impaired renal function (Table II). Comparable differences for MPA and MPAG PK parameters were observed between groups in particular immunosuppressive regimens; however, the differences for MPA C0 values were barely significant (Table III). In univariate analysis, MPAG PK parameters (AUC0-4 h, C0, Cmax) were negatively correlated with Ccr and positively correlated with serum creatinine (Figure 2). Within MPA PK parameters, only C0 was negatively correlated with Ccr and positively correlated with serum creatinine. Similar correlations were found in particular immunosuppressive regi- mens, although the serum creatinine correlation with MPA C0 in patients receiving MMF in combina- tion with CsA was statistically insignificant (Table IV). In multivariate analysis the results are consistent with univariate analysis. Additionally, some MPA and MPAG PK parameters were correlated with sex, CNI co-administered and body weight. No correlations with proteinuria were observed (Tables V and VI). For MPA and MPAG PK parameters, high CV val- ues were observed, which in patients with impaired B G 140 A PM l]120 ied /gm100 z μ lraom i[on80 -n rta60 e t isaodn cceonn4200 d eM 0 Arch Med Sci 1, February / 2012 0 1 2 Time [h] 3 4 0 1 2 Time [h] 3 4 CCr > 60 ml/min (n = 17) CCr < 60 ml/min (n = 26) Figure 1. Dose-corrected (A) mycophenolic acid (MPA) and (B) mycophenolic acid glucuronide (MPAG) concentration- time profiles classified by renal function (creatinine clearance (Ccr) > 60 ml/min vs. < 60 ml/ min). The results are presented as median ± standard deviation. Concentrations are corrected to a daily dose of 1 g mycophenolate mofetil