CYP3A5*3 and POR*28 Genetic Variants Influence the Required Dose of Tacrolimus in Heart Transplant Recipients

Abstract

Background: After heart transplantation (HTx), the interindividual pharmacokinetic variability of immunosuppressive drugs represents a major therapeutic challenge due to the narrow therapeutic window between over-immunosuppression causing toxicity and underimmunosuppression leading to graft rejection. Although genetic polymorphisms have been shown to influence pharmacokinetics of immunosuppressants, data in the context of HTx are scarce. We thus assessed the role of genetic variation in CYP3A4, CYP3A5, POR, NR1I2, and ABCB1 acting jointly in immunosuppressive drug pathways in tacrolimus (TAC) and ciclosporin (CSA) dose requirement in HTx recipients.Methods: Associations between 7 functional genetic variants and blood dose-adjusted trough (C 0 ) concentrations of TAC and CSA at 1, 3, 6, and 12 months after HTx were evaluated in cohorts of 52 and 45 patients, respectively.Results: Compared with CYP3A5 nonexpressors (*3/*3 genotype), CYP3A5 expressors (*1/*3 or *1/*1 genotype) required around 2.2-to 2.6-fold higher daily TAC doses to reach the targeted C 0 concentration at all studied time points (P # 0.003). Additionally, the POR*28 variant carriers showed higher dose-adjusted TAC-C 0 concentrations at all time points resulting in significant differences at 3 (P = 0.025) and 6 months (P = 0.047) after HTx. No significant associations were observed between the genetic variants and the CSA dose requirement.Conclusions: The CYP3A5*3 variant has a major influence on the required TAC dose in HTx recipients, whereas the POR*28 may additionally contribute to the observed variability. These results support the importance of genetic markers in TAC dose optimization after HTx.

CYP3A pharmacogenetics and tacrolimus disposition in adult heart transplant recipients

“…Our study is the largest to date to evaluate the impact of CYP3A5 genotype on tacrolimus disposition in adult heart transplant recipients. We found that mean tacrolimus C 0 /D was 1.8‐fold lower and tacrolimus TDD was 2‐fold higher in CYP3A5 expressers vs non‐expressers, which is similar in magnitude to previous reports . In our cohort, CYP3A5 expresser status accounted for about 24% of the variability in tacrolimus C 0 /D, which is also consistent with other studies .…”

IL-3 and CTLA4 gene polymorphisms may influence the tacrolimus dose requirement in Chinese kidney transplant recipients

“…The C/D ratio (ie, dose-adjusted drug C0) as an index of tacrolimus pharmacokinetics was used as an outcome variable. This ratio, defined as the drug C0 concentration per daily weightadjusted drug dose [(ng/mL)/(mg·kg -1 ·d -1 )], has commonly been used in other studies [25] . …”

A Lack of Significant Effect of POR*28 Allelic Variant on Tacrolimus Exposure in Kidney Transplant Recipients

“…17,18 Clinically, POR*28 may explain a part of calcineurin inhibitors (cyclosporine and Tac) variability, and POR*28 carriers may experience faster Tac metabolism. Indeed, it has been reported that POR*28 carriers have lower residual concentrations (C0) of cyclosporine and lower adjusted Tac C0 (Tac C0/Tac dose) in heart transplantation, 19 and adult 20,21 and pediatric 22 kidney transplantation. However, the strength of this association seems weak, 19,23 and the impact of POR*28 on Tac doses requirements is limited (15%-20%), compared with those mediated by CYP3A5 and CYP3A4 variants.…”

“…Indeed, it has been reported that POR*28 carriers have lower residual concentrations (C0) of cyclosporine and lower adjusted Tac C0 (Tac C0/Tac dose) in heart transplantation, 19 and adult 20,21 and pediatric 22 kidney transplantation. However, the strength of this association seems weak, 19,23 and the impact of POR*28 on Tac doses requirements is limited (15%-20%), compared with those mediated by CYP3A5 and CYP3A4 variants. 21,23 Whether POR genotyping should be integrated in routine pharmacogenetic screening before Tac introduction in solid organ transplantation is not established, and the definite proof on the clinical impact of this polymorphism remains to be validated by independent large-scale studies.…”