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. 2024 Jan 8:14:1334440.
doi: 10.3389/fphar.2023.1334440. eCollection 2023.

CYP3A5 influences oral tacrolimus pharmacokinetics and timing of acute kidney injury following allogeneic hematopoietic stem cell transplantation

Nathan D Seligson  1   2   3 , Xunjie Zhang  1 , Mark C Zemanek  1 , Jasmine A Johnson  1 , Zachary VanGundy  1 , Danxin Wang  4 , Mitch A Phelps  3   5 , Julianna Roddy  1   2 , Craig C Hofmeister  6 , Junan Li  3   7 , Ming J Poi  1   2   3
Affiliations

CYP3A5 influences oral tacrolimus pharmacokinetics and timing of acute kidney injury following allogeneic hematopoietic stem cell transplantation

Nathan D Seligson et al. Front Pharmacol. .

Abstract

Introduction: Polymorphisms in genes responsible for the metabolism and transport of tacrolimus have been demonstrated to influence clinical outcomes for patients following allogeneic hematologic stem cell transplant (allo-HSCT). However, the clinical impact of germline polymorphisms specifically for oral formulations of tacrolimus is not fully described. Methods: To investigate the clinical impact of genetic polymorphisms in CYP3A4, CYP3A5, and ABCB1 on oral tacrolimus pharmacokinetics and clinical outcomes, we prospectively enrolled 103 adult patients receiving oral tacrolimus for the prevention of graft-versus-host disease (GVHD) following allo-HSCT. Patients were followed in the inpatient and outpatient phase of care for the first 100 days of tacrolimus therapy. Patients were genotyped for CYP3A5 *3 (rs776746), CYP3A4 *1B (rs2740574), ABCB1 exon 12 (rs1128503), ABCB1 exon 21 (rs2032582), ABCB1 exon 26 (rs1045642). Results: Expression of CYP3A5 *1 was highly correlated with tacrolimus pharmacokinetics in the inpatient phase of care (p < 0.001) and throughout the entirety of the study period (p < 0.001). Additionally, Expression of CYP3A5 *1 was associated with decreased risk of developing AKI as an inpatient (p = 0.06). Variants in ABCB1 were not associated with tacrolimus pharmacokinetics in this study. We were unable to discern an independent effect of CYP3A4 *1B or *22 in this population. Conclusion: Expression of CYP3A5 *1 is highly influential on the pharmacokinetics and clinical outcomes for patients receiving oral tacrolimus as GVHD prophylaxis following allo-HSCT.

Keywords: CYP3A4; CYP3A5; hematologic stem cell transplant; precision medicine; single nucleotide polymorphism; tacrolimus.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision.

Figures

FIGURE 1
FIGURE 1
Expressers of CYP3A5 *1 exhibited lower normalized tacrolimus concentration across the first 100 days of therapy. Red lines represent the median and interquartile range. ns, not significant; *, p < 0.05; **, p < 0.01; ***, p < 0.001, ****, p < 0.0001.
FIGURE 2
FIGURE 2
CYP3A5 *1 expressers experienced lower initial tacrolimus levels and required increased doses of tacrolimus at discharge. (A) The weight adjusted tacrolimus dose increased during the inpatient stay for CYP3A5 *1 expressers while the opposite was true for CYP3A5 *3/*3 patients. (B) There was a significant difference in the tacrolimus levels achieved in patients grouped by CYP3A5 genotype up until day 10 of therapy. (C) Patients with a CYP3A5 *3/*3 genotype were discharged on lower weight adjusted doses of tacrolimus to their starting dose. ns, not significant; *, p < 0.05; **, p < 0.01; ***, p < 0.001, ****, p < 0.0001.
FIGURE 3
FIGURE 3
Proportion of patients achieving therapeutic levels of tacrolimus over the first 60 days of tacrolimus therapy by CYP3A5 status. ns, not significant; *, p < 0.05; **, p < 0.01; ***, p < 0.001, ****, p < 0.0001.
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