Circadian and time-dependent variability in tacrolimus pharmacokinetics

Tacrolimus (TAC) is considered a critical dose drug. The purpose of our study was to investigate circadian and time-dependent changes in TAC pharmacokinetics over the first year after kidney transplantation. Pharmacokinetic (PK) studies were performed in 26 recipients of first living donor kidney transplants at day 7 after morning (a.m.) and evening (p.m.) doses of TAC. Additional serial PK studies were carried out in nine patients at month 6 (M6) and month 12 (M12). Blood samples were collected before 1, 1.5, 2, 2.5, 3, 4, 6, 8 and 12 h after TAC administration. Demographics, TAC and adjunctive immunosuppressive doses, hematology, and biochemistry were recorded in each PK study. Mean age was 37 years, body mass index 23 kg/m(2), 58% males, and 85% Caucasian. Higher AUC (231.4 vs. 220 ng.h/mL, P = 0.06) and C-max (34.1 +/- 12.6 vs. 24.4 +/- 9.8 ng/mL, P < 0.001), and lower T-max (1.6 +/- 0.8 vs. 2.7 +/- 2.0 h, P = 0.05) values were observed comparing a.m. and p.m. administrations. Comparing D7, M6 and M12, there was a significant increase in dose-normalized AUC (31.4 +/- 22.2 vs. 50.1 +/- 33 vs. 39.2 +/- 24.4 ng.h/mL/mg, P = 0.005), C-max (4.4 +/- 2.4 vs. 7.8 +/- 3.5 vs. 6.0 +/- 3.3 ng/mL/mg, P < 0.001) and T-max (1.6 +/- 1.1 vs. 1.7 +/- 0.4 vs. 1.8 +/- 0.8 h, P = 0.006), respectively. Over the first year the intraindividual variability of dose-normalized AUC, C-max and C-0 were 82%, 72%, and 90%, respectively. No significant changes were observed comparing inter-individual variability of dose-normalized AUC (21%, 24%, 33%), C-max (46%, 45%, 55%), C-0 (49%, 83%, 81%) at D7, M6 and M12, respectively. We observed a good correlation between a.m. and p.m. TAC AUC (r(2) = 0.90) and C-0 (r(2) = 0.88). Tacrolimus pharmacokinetics display circadian variation suggesting a slower and delayed absorption phase at nighttime. Tacrolimus also showed time-dependent PK changes, suggesting an improvement in absorption during the first 6 months. Despite circadian variation we observed good correlations between a.m. and p.m. TAC AUC (r(2) = 0.90) and C-0 (r(2) = 0.88) and between C-0 and total daily TAC exposure (a.m. + p.m. AUC) suggesting that trough-guided therapeutic monitoring is still a reliable and simple strategy to optimize the clinical use of TAC.