Clinical Impact of the Adaptation of Initial Tacrolimus Dosing to the CYP3A5 Genotype After Kidney Transplantation: Systematic Review and Meta-Analysis of Randomized Controlled Trials

Objective The aim of this systematic review and meta-analysis was to compare the clinical outcomes between genotype-guided and conventional tacrolimus doses in kidney transplantation patients. Materials and Methods We performed a comprehensive literature search of the PubMed, EMBASE, and Cochrane databases from the date of inception to 26 February 2020. References of the retrieved articles were also reviewed and any further relevant studies were included. The search terms included 'tacrolimus', 'cytochrome P-450 CYP3A', 'polymorphism, genetic', 'genomics', 'genome', 'genotype', 'genes', 'alleles', and 'pharmacogenetics'. Results Our study showed that the genotype-guided group included an increased proportion of patients with tacrolimus concentrations in the therapeutic range at steady state (risk ratio [RR] 1.40, 95% confidence interval [CI] 1.14-1.72, p = 0.001; high quality), with a trend for achieving therapeutic concentrations earlier compared with those in the conventional group. However, there was no statistical difference in the incidence of delayed graft function (RR 1.98, 95% CI 0.92-1.76, p = 0.12; moderate quality), incidence of acute rejection (RR 1.00, 95% CI 0.64-1.55, p = 1.00; moderate quality), incidence of graft survival censored for death (RR 1.02, 95% CI 0.98-1.06, p = 0.37; moderate quality), and incidence of adverse effects (AEs). Conclusions Although the genotype-guided group had a higher proportion of patients within the targeted concentration and less median time to achieve the therapeutic range, the clinical endpoints, including delayed graft function, acute rejection, graft survival censored for death, and AEs were similar in both groups. All in all, evidence suggested there was no utility in pharmacogenetics for tacrolimus based on the cytochrome P450 (CYP) 3A5 genotype. Studies with Chinese and African American populations are needed due to the frequency of genetic polymorphisms of CYP3A5. Furthermore, a dosing algorithm that includes demographic and clinical factors plus multiple genetic variants should be added for consideration, and may optimize early tacrolimus exposure.

Automated summary

The study found that in kidney transplantation patients, genotype-guided tacrolimus dosing led to more patients having therapeutic tacrolimus concentrations in the targeted range and achieving therapeutic levels faster compared to conventional dosing. However, there were no statistical differences in clinical endpoints including delayed graft function, acute rejection, graft survival, and adverse effects between the two groups. The study suggested that pharmacogenetics based on CYP3A5 genotype did not provide utility in optimizing tacrolimus dosing.