Gender-dependent predictable pharmacokinetic method for tacrolimus exposure monitoring in kidney transplant patients

Abstract

Tacrolimus (Tac) is an immunosuppressive drug with a narrow therapeutic width and highly variable pharmacokinetics. Therefore, monitoring of Tac blood concentrations is of utmost importance in the management of renal transplant recipients. The occurrence and intensity of adverse effects depend on blood concentration and total exposure of the organism to this drug. This implies finding a new gender-dependent predictable method for Tac exposure monitoring based on determination of the area under the time concentration curve (AUC). The primary aim of this study was to investigate gender differences in systemic body exposure to Tac in renal transplant patients after the first oral dose and in a steady state by determining 12-h AUC (AUC(0-12)). The secondary objective was to find the best sampling time in which measured Tac concentration best predicts AUC value with respect to gender. Tac pharmacokinetic study was conducted in 20 kidney transplant recipients (10 men/10 women) on quaternary immunosuppressive therapy. The first oral Tac dose (0.05 mg/kg) was given on the fifth day post-transplant. After reaching steady state, regimen stabilized and dosage was adjusted in accordance with the level of Tac. Blood concentrations were measured by microparticle enzyme immunoassay method. AUC(0-12) for each patient was calculated after the first oral Tac dose and in the steady state from a plot of Tac concentration versus time from 0 to 12 h using the trapezoid rule. Associations between each sampling time point of concentrations within 12 h after the administration and AUC(0-12) were evaluated by Pearson correlation coefficients. Abbreviated sampling equations were derived by multiple stepwise regression analyses. Statistically significant difference was found in AUC(0-12) between male and female patients after the first oral dose (p < 0.01), but this difference was lost in a steady state. In female recipients C(2) seemed to be good indicator of total body exposure to Tac after the first oral dose and this was also confirmed in a steady state. The three-point sampling method was required for calculating AUC after the first oral dose in male patients, whereas in the steady state, concentration of C(8) seemed to be a good indicator of abbreviated AUC for a Tac monitoring strategy in male patients. Non-compartment Tac pharmacokinetic and regression analysis showed gender difference in total Tac exposure and determined the best predictable Tac concentrations after the first oral dose. Our study confirmed gender-dependent pharmacokinetics in a steady state in terms of best sampling time in which measured Tac concentration best predicts AUC value.