AUTHOR=Seligson Nathan D. , Zhang Xunjie , Zemanek Mark C. , Johnson Jasmine A. , VanGundy Zachary , Wang Danxin , Phelps Mitch A. , Roddy Julianna , Hofmeister Craig C. , Li Junan , Poi Ming J. 

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

JOURNAL=Frontiers in Pharmacology

VOLUME=14

YEAR=2024

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2023.1334440

DOI=10.3389/fphar.2023.1334440

ISSN=1663-9812

ABSTRACT=<p><bold>Introduction:</bold> 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.</p><p><bold>Methods:</bold> To investigate the clinical impact of genetic polymorphisms in <italic>CYP3A4</italic>, <italic>CYP3A5</italic>, and <italic>ABCB1</italic> 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 <italic>CYP3A5</italic> *3 (rs776746), <italic>CYP3A4</italic> *1B (rs2740574), <italic>ABCB1</italic> exon 12 (rs1128503), <italic>ABCB1</italic> exon 21 (rs2032582), <italic>ABCB1</italic> exon 26 (rs1045642).</p><p><bold>Results:</bold> Expression of <italic>CYP3A5</italic> *1 was highly correlated with tacrolimus pharmacokinetics in the inpatient phase of care (<italic>p</italic> &lt; 0.001) and throughout the entirety of the study period (<italic>p</italic> &lt; 0.001). Additionally, Expression of <italic>CYP3A5</italic> *1 was associated with decreased risk of developing AKI as an inpatient (<italic>p</italic> = 0.06). Variants in <italic>ABCB1</italic> were not associated with tacrolimus pharmacokinetics in this study. We were unable to discern an independent effect of <italic>CYP3A4</italic> *1B or *22 in this population.</p><p><bold>Conclusion:</bold> Expression of <italic>CYP3A5</italic> *1 is highly influential on the pharmacokinetics and clinical outcomes for patients receiving oral tacrolimus as GVHD prophylaxis following allo-HSCT.</p>