Association of P450 Oxidoreductase Gene Polymorphism with Tacrolimus Pharmacokinetics in Renal Transplant Recipients: A Systematic Review and Meta-Analysis

Abstract

There are conflicting results regarding the effect of the P450 oxidoreductase (POR) *28 genotype on the tacrolimus (TAC) pharmacokinetics (PKs) during the early post-transplantation period in adult renal transplant recipients. Thus, we characterized the impact of POR*28 on TAC PKs. We conducted a systematic review on the association between POR*28 and PKs of TAC in adult renal transplant recipients. Structured searches were conducted using PubMed, Web of Science, and Embase. TAC standardized trough concentration (ng/mL per mg/kg) data were extracted. Mean differences (MD) and their corresponding 95% confidence intervals (CIs) were used to identify the differences between the POR*28 genotype and PKs of TAC. The subgroup analysis was conducted according to CYP3A5 expression status. Six studies (n = 1061) were included. TAC standardized trough concentrations were significantly lower in recipients with the POR*28 allele compared to recipients with POR*1/*1 (MD: 8.30 ng/mL per mg/kg; 95% CI: 1.93, 14.67; p = 0.01). In the subgroup analysis, TAC standardized trough concentrations were lower for subjects who were POR*28 carriers than those who were POR*1/*1 in CYP3A5 expressers (MD: 20.21 ng/mL per mg/kg; 95% CI: 16.85, 23.56; p < 0.00001). No significant difference between POR*28 carriers and POR*1/*1 was found in the CYP3A5 non-expressers. The results of our meta-analysis demonstrated a definite correlation between the POR*28 genotype and PKs of TAC. Patients carrying the POR*28 allele may require a higher dose of TAC to achieve target levels compared to those with POR*1/*1, especially in CYP3A5 expressers.