J Korean Med Sci.  2022 Feb;37(5):e33. 10.3346/jkms.2022.37.e33.

Flat Pattern Peaks of Tacrolimus Absorption and Associated Pharmacogenomic Variants in Kidney Transplantation Recipients

• Kim SM
• Lim Y
• Min S
• Min BJ
• Seo ME
• Lee KH
• Kim JH
• Ha J

• KMID: 2525485
• DOI: http://doi.org/10.3346/jkms.2022.37.e33

Abstract

Background
Tacrolimus is the most commonly used immunosuppressive drug in solid organ transplantation. After administering a conventional twice-daily dose of tacrolimus, peak levels were achieved within the first 1.5 to 2 hours. A group of patients showed different early absorption phase of tacrolimus after kidney transplantation.
Methods
Trough(C₀ ) and 1.5-hour blood levels (C_1.5 ) of tacrolimus were measured in 95 kidney transplantation recipients. Patients with a C_1.5 /C₀ < 1.5 and > 1.5 were defined as those having flat pattern peaks and as controls, respectively. Transplantation outcomes were compared between the groups. Whole exome sequencing was performed to investigate the genetic susceptibility to flat pattern peaks.
Results
Twenty-eight patients showed flat pattern peaks. The mean C_1.5 /C₀ values were 1.13 ± 0.22 and 3.78 ± 1.25 in the flat pattern peak and control groups, respectively. In multivariate analysis, flat pattern peak was an independent risk factor for biopsy-proven acute rejection (BPAR) and/or borderline change (P = 0.014). Patients having flat pattern peaks showed significantly lower post-transplant 36-month estimated glomerular filtration rate (P = 0.001). Two single nucleotide variants in ABCB1 genes, rs1922242 and rs2235035, were associated with flat pattern peaks (P = 0.019 and P = 0.027, respectively).
Conclusion
Both of C_1.5 and C₀should be measured to distinguish the patients showing unique initial absorption. A C_1.5 /C₀ ratio lower than 1.5 was associated with an increased risk of BPAR and/or borderline change. Single nucleotide variants s in ABCB1 gene might influence the flat pattern peaks of tacrolimus absorption.

Keyword

Tacrolimus; Kidney Transplantation; Pharmacogenomics

Figure

• 

  Fig. 1 A representative time-concentration curve of tacrolimus of each group. (A) Flat pattern peak group showed the similar tacrolimus level observed immediately before the administration and 1 to 4 hours after administration and (B) control group showed the peak levels achieved within the first 1.5 to 2 hours after administration of a conventional twice-daily dose of tacrolimus.

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