Impact of Pharmacogenetics on Intravenous Tacrolimus Exposure and Conversions to Oral Therapy

Pasternak, Amy L; Marcath, Lauren A.; Nguyen, Vy; Gersch, Christina L.; Rae, James M.; Frame, David; Scappaticci, Gianni B.; Kidwell, Kelley M.; Hertz, Daniel L

doi:10.1016/j.jtct.2021.09.011

Cited by 8 publications

(1 citation statement)

References 29 publications

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“…Given the potential for intestinal metabolism, as well as first-pass hepatic metabolism prior to reaching systemic circulation, the effect of genomic variants on tacrolimus administered orally poses an additional level of complexity in comparison to intravenous tacrolimus. While significant data exists demonstrating the role of pharmacogenomic variants on oral tacrolimus outside of allo-HSCT ( Goto et al, 2004 ; Kato et al, 2018 ; Pasternak et al, 2019 ; Pasternak et al, 2022 ), this data may not fully apply in the setting of allo-HSCT given the differences in tacrolimus dosing and a desire for less aggressive early tacrolimus levels to confer a graft-versus-leukemia effect ( Imado et al, 2004 ). It is therefore possible that existing findings using intravenous formulations of tacrolimus in the setting of allo-HSCT, and those of oral tacrolimus outside of allo-HSCT, may not fully reflect the pharmacogenomic implications of tacrolimus metabolism specific to the oral route in an allo-HSCT population.…”

Section: Introductionmentioning

confidence: 99%

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

Seligson,

Zhang,

Zemanek

et al. 2024

Front. Pharmacol.

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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.

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