# Cohort Study to Determine the Impact of CYP3A5 Genotype on Tacrolimus Dosing Requirements and Trough Concentrations in Heart Transplant Recipients

## TL;DR

This study shows that heart transplant patients who express the CYP3A5 gene need higher doses of tacrolimus and take longer to reach effective drug levels, suggesting personalized dosing based on genetic factors could improve treatment outcomes.

## Contribution

The study provides empirical evidence that CYP3A5 genotype significantly affects tacrolimus dosing and time to therapeutic concentration in heart transplant recipients.

## Key findings

- CYP3A5 expressers took longer to reach therapeutic tacrolimus levels compared to non-expressers.
- Expressers required nearly double the tacrolimus dose to achieve target concentrations.
- Non-expressers had higher dose-adjusted tacrolimus trough concentrations.

## Abstract

Tacrolimus is primarily metabolized by Cytochrome P450 (CYP)3A4/5. The Clinical Pharmacogenetics Implementation Consortium recommends increasing the initial dose 1.5‐ to 2‐fold in CYP3A5 expressers to enhance transplant outcomes. Our objective was to investigate the impact of CYP3A5 expresser status on tacrolimus dosing requirements and attainment of target trough concentrations in heart transplant recipients.

We performed a retrospective cohort analysis of tacrolimus dose, concentration, demographics, CYP3A4/5 genotype, concomitant medications, and biochemical data in heart transplant recipients from December 2020 to August 2023. The primary outcome was the time to first therapeutic trough concentration, compared by CYP3A5 expression status. Secondary outcomes included the tacrolimus dose at target trough and dose‐adjusted tacrolimus trough concentration (C0/D). Stepwise multiple regression was performed to account for potential covariates. Moreover, clinical outcomes were assessed at 1‐year post‐transplantation and compared based on CYP3A5 expression status.

Among 33 patients, CYP3A5 expressers (27.3%) required longer to achieve therapeutic trough concentrations (median [Q1, Q3]: expressers: 14 [9.5, 16] days vs. nonexpressers 7.5 [6.0, 11] days; p = 0.0073) and required nearly double the tacrolimus dose to reach target concentrations (10 [5.5, 13] mg/day for expressers vs. 5 [3.3, 5.9] mg/day for nonexpressers; p = 0.0019). Conversely, the C0/D was nearly 2‐fold higher in nonexpressers 2.0 [1.6, 3.4] ng/(mL*mg) than expressers (1.1 [0.83, 1.7] ng/(mL*mg); p = 0.0015). Stepwise regression identified route of administration (sublingual vs. oral) at therapeutic trough and initial dose as covariates for all outcomes. All clinical outcomes showed no significant differences based on CYP3A5 expression status, with the exception that poor metabolizers demonstrated higher serum creatinine elevation at 1‐week post‐transplantation (p = 0.047).

Our findings highlight the impact of CYP3A5 expresser status on the time needed and dosing requirements to attain tacrolimus therapeutic concentrations in heart transplant recipients, suggesting CYP3A5‐guided dosing strategies may improve rapid attainment of therapeutic tacrolimus concentrations.