Circadian and time-dependent variability in tacrolimus pharmacokinetics

• Published in: Fundamental & clinical pharmacology Vol. 21; no. 2; pp. 191 - 197
• Main Authors: Park, Sung-In, Felipe, Claudia R., Pinheiro-Machado, Paula G., Garcia, Riberto, Tedesco-Silva Jr, Helio, Medina-Pestana, Jose O.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.04.2007; Blackwell
• Subjects: Adult; Area Under Curve; Biological and medical sciences; circadian; Circadian Rhythm; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Monitoring; Enzyme-Linked Immunosorbent Assay; Female; Humans; immunosuppression; Immunosuppressive Agents - pharmacokinetics; kidney transplant; Kidney Transplantation; Male; Medical sciences; Middle Aged; pharmacokinetic; Pharmacology. Drug treatments; tacrolimus; Tacrolimus - pharmacokinetics; Time Factors; time-dependent; Variability; kidney transplant; Lactone; Biological rhythm; Transplantation; Circadian rhythm; Macrolide; Kidney; Immunomodulator; Immunosuppression; circadian; Treatment; Urinary system; Tacrolimus; Surgery; Graft; time-dependent; Protein synthesis inhibitor; Immunosuppressive agent; Pharmacokinetics; pharmacokinetic. tacrolimus
• ISSN: 0767-3981; 1472-8206
• DOI: 10.1111/j.1472-8206.2007.00468.x

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/m2, 58% males, and 85% Caucasian. Higher AUC (231.4 vs. 220 ng·h/mL, P = 0.06) and Cmax (34.1 ± 12.6 vs. 24.4 ± 9.8 ng/mL, P < 0.001), and lower Tmax (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), Cmax (4.4 ± 2.4 vs. 7.8 ± 3.5 vs. 6.0 ± 3.3 ng/mL/mg, P < 0.001) and Tmax (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, Cmax and C0 were 82%, 72%, and 90%, respectively. No significant changes were observed comparing inter‐individual variability of dose‐normalized AUC (21%, 24%, 33%), Cmax (46%, 45%, 55%), C0 (49%, 83%, 81%) at D7, M6 and M12, respectively. We observed a good correlation between a.m. and p.m. TAC AUC (r2 = 0.90) and C0 (r2 = 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 (r2 = 0.90) and C0 (r2 = 0.88) and between C0 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.