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. 2022 Jul 1;32(5):209-217.
doi: 10.1097/FPC.0000000000000472. Epub 2022 Apr 7.

Composite CYP3A phenotypes influence tacrolimus dose-adjusted concentration in lung transplant recipients

Michelle Liu  1 , Ciara M Shaver  2 , Kelly A Birdwell  3 , Stephanie A Heeney  1 , Christian M Shaffer  4 , Sara L Van Driest  4   5
Affiliations

Composite CYP3A phenotypes influence tacrolimus dose-adjusted concentration in lung transplant recipients

Michelle Liu et al. Pharmacogenet Genomics. .

Abstract

Objectives: Interpatient variability in tacrolimus pharmacokinetics is attributed to metabolism by cytochrome P-450 3A4/5 isoenzymes (encoded by CYP3A4 and CYP3A5). Guidelines for adjusting tacrolimus based on CYP3A5 test results are published; however, CYP3A4 variants also contribute to the variability in tacrolimus pharmacokinetics. The effects of composite phenotypes incorporating CYP3A5 and CYP3A4 increased (*1G, *1B) and decreased (*22) function variants have not been evaluated. The objective of this study is to investigate the impact of both increased and decreased function CYP3A variants on weight and dose-adjusted tacrolimus concentration (C0/D).

Methods: We performed a single-center retrospective cohort study of lung transplant recipients to evaluate the median tacrolimus C0/D by composite CYP3A phenotype groups during the index transplant hospitalization. CYP3A4 and CYP3A5 alleles were used to classify patients into four CYP3A groups from least to most CYP3A activity. Exploratory analyses of ABCB1 and additional candidate genes were also assessed.

Results: Of the 92 included individuals, most (58) were CYP3A Group 2. The median tacrolimus C0/D differed significantly between CYP3A groups (P = 0.0001). CYP3A Group 2 median tacrolimus C0/D was 190.5 (interquartile range: 147.6-267.5) (ng/ml)/(mg/kg/d) and significantly higher than Group 4 [107.9 (90.4-116.1), P = 0.0001)]. Group 2 median tacrolimus C0/D did not significantly differ from Group 1 and Group 3 [373.5 (149.2-490.3) and 81.4 (62.6-184.1), respectively]. No significant differences in tacrolimus C0/D were found for the ABCB1 diplotypes.

Conclusion: These data indicate that a composite CYP3A phenotype incorporating both increase and decrease variant information from CYP3A4 in addition to CYP3A5 may significantly influence tacrolimus C0/D during the early postoperative period.

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Conflict of interest statement

Conflicts of interest: All other authors declared no competing interests for this work.

Figures

Figure 1.
Figure 1.. Tacrolimus dose-adjusted concentration by CYP3A phenotypes
Individual patients represented by dots overlaying box and whisker plot of the median dose and weight-adjusted tacrolimus concentration (C0/D) by CYP3A phenotypes ((Group 1 (n=11), Group 2 (n=58), Group 3 (n=6), and Group 4 (n=17)). The line within the box plot represents the median value, while the box represents the interquartile range (IQR) and the whiskers represents the minimum and maximum values (excluding outliers), respectively.
Figure 2.
Figure 2.. Relationship between weight-adjusted tacrolimus dose at discharge and CYP3A phenotypes
Individual dose requirements at discharge represented by dots overlaying box and whisker plot by CYP3A phenotypes (Group 1 (n=11), Group 2 (n=58), Group 3 (n=6), and Group 4 (n=17)). The line within the box plot represents the median value, while the box represents the IQR and the whiskers represents the minimum and maximum values (excluding outliers), respectively.
Figure 3 a, b.
Figure 3 a, b.. Frequency of subtherapeutic and supratherapeutic exposures to tacrolimus by CYP3A phenotypes
Individual patients represented by dots overlaying box and whisker plot of the percent subtherapeutic and supratherapeutic tacrolimus concentrations by CYP3A phenotypes. The line within the box plot represents the median value, while the box represents the IQR and the whiskers represents the minimum and maximum values (excluding outliers), respectively.
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References

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