Effects of the CYP3A4 ô 1B genetic polymorphism on the pharmacokinetics of tacrolimus in adult renal transplant recipients: A meta-analysis

Abstract

Background and Objective The association between the CYP3A4∗1B single nucleotide polymorphism (SNP) and tacrolimus pharmacokinetics in different studies is controversial. Therefore, a meta-analysis was employed to evaluate the correlation between the CYP3A4∗1B genetic polymorphism and tacrolimus pharmacokinetics at different post-transplantation times in adult renal transplant recipients. Methods Studies evaluating the CYP3A4∗1B genetic polymorphism and tacrolimus pharmacokinetics were retrieved through a systematical search of Embase, PubMed, the Cochrane Library, ClinicalTrials.gov and three Chinese literature databases (up to Sept. 2014). The pharmacokinetic parameters (weight-adjusted tacrolimus daily dose and tacrolimus trough concentration/weight-adjusted tacrolimus daily dose ratio) were extracted, and the metaanalysis was performed using Stata 12.1. Results Seven studies (involving 1182 adult renal transplant recipients) were included in this metaanalysis. For the weight-adjusted tacrolimus daily dose, in all included renal transplant recipients (European & Indian populations), CYP3A4∗1/∗1 recipients required a significantly lower weight-adjusted tacrolimus daily dose than did CYP3A4∗1B carriers at 7 days (WMD -0.048; 95% CI -0.083 ∼ -0.014), 6 months (WMD -0.058; 95% CI -0.081 ∼ -0.036) and 12 months (WMD - 0.061; 95% CI -0.096 ∼ -0.027) post-transplantation. In light of the heterogeneity, the analysis was repeated after removing the only study in an Indian population, and CYP3A4∗1/∗1 European recipients (mostly Caucasian) required a lower weightadjusted tacrolimus daily dose within the first year post-transplantation. The tacrolimus trough concentration/weight-adjusted tacrolimus daily dose ratio (C0/Dose ratio) was significantly higher in CYP3A4∗1/∗1 recipients than in CYP3A4∗1B carriers at 6 months (WMD 52.588; 95% CI 22.387 ∼ 82.789) and 12 months (WMD 62.219; 95% CI 14.218 ∼ 110.221) post-transplantation. When the only study in an Indian population was removed to examine European recipients (mostly Caucasian), the significant difference persisted at 1 month, 6 months and 12 months post-transplantation. Conclusion Based on our meta-analysis, the CYP3A4∗1B genetic polymorphism affects tacrolimus dose requirements and tacrolimus trough concentration/weight-adjusted tacrolimus daily dose ratio within the first year post-transplantation in adult renal transplant recipients, especially in European recipients (mostly Caucasian).