Clinical pharmacokinetics of tacrolimus after the first oral administration in combination with mycophenolate mofetil and prednisone in Chinese renal transplant recipients

Introduction. Data on tacrolimus pharmacokinetics in combination with mycophenolate mofetil and prednisone are scarce in Chinese renal transplantation recipients. The purpose of this study was to detect interpatient pharmacokinetic variability of tacrolimus and to assess the predictability of individual tacrolimus concentrations at various times for the area under the curve (AUC) seeking to find the best sampling time for an abbreviated AUC to predict the total body exposure of tacrolimus after the first oral dose in Chinese renal transplantation recipients. Methods. Sixteen primary kidney transplant recipients were treated with methylprednisolone and antilymphocyte globulin for 3 days. The first tacrolimus oral dose (0.075 mg/kg) was given at day 3 posttransplant. Mycophenolate mofetil and prednisone were administered orally posttransplant. Blood samples were obtained at 0.5, 1.0, 1.5, 2.0, 3.0, 5.0, 8.0, and 12.0 hours after taking the first oral dose. Tacrolimus blood concentrations were measured by ELISA. Twelve-hour AUC (AUC(12)) for each patient was calculated using the linear trapezoid rule. Associations between the blood concentration at each sampling time point and the AUC(12) were evaluated by Pearson correlation coefficients. Abbreviated sampling equations were derived by multiple, stepwise regression analyses performed using AUC(12) as the dependent variables. The variance in the strength of association between predicted AUC (AUC(P)) and AUC(12) was reflected by linear regression coefficients of multiple determinations. Results. In 16 patients, AUC(12) values were within the range of 44.40 ng (.) h/mL to 158.01 ng (.) h/mL (mean = 92.23 +/- 34.97 ng (.) h/mL). The area of the maximum AUC(12) was almost fourfold higher than that of the minimum AUC(12). C-12 significantly correlated with AUC12 after the first tarcrolimus oral dose (r = .846, P < .001). C-5, C-8, and C-3 showed better correlations: r = .924, .924, and .911, respectively. From stepwise multiple regression, C-5 seemed to be the best predictor of total body exposure to tacrolimus (r = .92, r(2) = .85). Alternatively, the concentrations at 5 and 1.5 hours or 5, 1.5, and 3 hours as an abbreviated AUC were as good as a full pharmacokinetic study (r = .97, r(2) = .94, and r = .99, r(2) = .99, respectively). Conclusions. Tacrohmus AUC12 show remarkable interindividual variations after the first oral dose in combination with mycophenolate mofetil and predrisone in Chinese renal transplant recipients. Although C12 is a good predictor of efficacy, C5 might be the best predictor of the first AUC(12). A two-point sampling method using C-5 and C-1.5 or three-point sampling method using C-5, C-1.5, and C-3 might be the best abbreviated AUC for a cost-effective tacrolimus monitoring strategy.