Studies on the effect of everolimus on tacrolimus pharmacokinetics (PK) were limited and the results were inconsistent. In contrast, studies showed there was little effect of mycophenolate mofetil (MMF) on tacrolimus PK. This study investigated the influence of everolimus on tacrolimus PK, using MMF-tacrolimus combination as a control.

This was a prospective, randomized, open-label study. De novo renal transplant recipients aged 20-65 years were included. Exclusion criteria were pregnancy, retransplantation or multiorgan transplantation, positive for human immunodeficiency virus, hepatitis B or C virus, aminotransferase level higher than two times the upper limit of normal, and history of rheumatoid arthritis. Patients were randomized to receive either everolimus (1 mg bid) or MMF (10-15 mg/kg bid) in combination with tacrolimus and corticosteroids. Doses of tacrolimus were adjusted to maintain trough concentration (C_trough) in the range of 8-12 ng/mL. Steady-state PK profiles of tacrolimus and everolimus using whole blood sample were analyzed predose and 1, 2, 3, 5, 8, 12 hours postdose. PK parameters were analyzed by noncompartmental method. Continuous variables and categorical variables were analyzed by unpaired two-tailed t test and Fisher's exact test, respectively.

Twelve patients completed the study, with six in each group. There were no significant differences in patient demographic between two groups. Tacrolimus doses required to maintain the same target C_trough were two times higher in everolimus-treated patients than in those treated with MMF (5.0 ± 1.3 vs. 2.5 ± 0.7 mg bid; P = 0.002). Dose-normalized tacrolimus area under the curve (AUC_0-12) (29.00 ± 6.22 vs. 55.14 ± 17.32 hr*ng/mL/mg, P = 0.012), dose-normalized tacrolimus C_trough (1.23 ± 0.32 vs. 3.13 ± 1.15 ng/mL/mg, P = 0.009), and dose-normalized tacrolimus peak concentration (C_max) (5.32 ± 1.31 vs. 8.48 ± 1.85 ng/mL/mg, P = 0.009) were significantly lower in patients who received everolimus than in those who received MMF.

In conclusion, tacrolimus exposure was significantly lower in everolimus-treated patients than those treated with MMF after kidney transplant. Tacrolimus doses should be adjusted, and C_trough should be closely monitored when switch between everolimus and MMF combination.

CITATION INFORMATION: Chang H.-P, Lee C.-Y, Si C.-C, Tsai M.-K, Lin Wu F.-L. Significant Pharmacokinetic Interaction Between Everolimus and Tacrolimus in De Novo Renal Transplant Recipients. Am J Transplant. 2016;16 (suppl 3).

« Back to 2016 American Transplant Congress