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 (AUC12) for each patient was calculated using the linear trapezoid rule. Associations between the blood concentration at each sampling time point and the AUC12 were evaluated by Pearson correlation coefficients. Abbreviated sampling equations were derived by multiple, stepwise regression analyses performed using AUC12 as the dependent variables. The variance in the strength of association between predicted AUC (AUC(P)) and AUC12 was reflected by linear regression coefficients of multiple determinations.

RESULTS

In 16 patients, AUC12 values were within the range of 44.40 ng x h/mL to 158.01 ng x h/mL (mean = 92.23 +/- 34.97 ng x h/mL). The area of the maximum AUC12 was almost fourfold higher than that of the minimum AUC12. C12 significantly correlated with AUC(12) after the first tarcrolimus oral dose (r = .846, P < .001). C5, C8, and C3 showed better correlations: r = .924, .924, and .911, respectively. From stepwise multiple regression, C5 seemed to be the best predictor of total body exposure to tacrolimus (r = .92, r2 = .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, r2 = .94, and r = .99, r2 = .99, respectively).

CONCLUSIONS

Tacrolimus AUC12 show remarkable interindividual variations after the first oral dose in combination with mycophenolate mofetil and prednisone in Chinese renal transplant recipients. Although C12 is a good predictor of efficacy, C5 might be the best predictor of the first AUC12. A two-point sampling method using C5 and C1.5 or three-point sampling method using C5, C1.5, and C3 might be the best abbreviated AUC for a cost-effective tacrolimus monitoring strategy.