Effect of CYP3A5*1 expression on tacrolimus required dose after liver transplantation: A systematic review and meta‐analysis

Abstract

We systematically collected eligible data to measure the effect of CYP3A5*1 expression on personalized tacrolimus therapy. Six databases were searched for studies on adult liver transplant recipients and donors of liver graft which reported tacrolimus dose requirement, trough blood concentration, and/or concentration/dose (C/D) ratio in expressers and nonexpressers of CYP3A5*1. Eligible data were pooled by meta-analysis. Sixteen observational studies (1309 recipients, 1044 donors of liver graft) were included in the analyses. Tacrolimus C/D ratio was lower, and the dose was higher in recipient expressers of CYP3A5*1 and/or carriers of expresser liver graft at 1-4 weeks and 2-4, 6, and 12 months post-transplantation. Tacrolimus blood concentration was lower at the first two weeks. Pair expressers were affected by about twofold, and the effect was different between ethnic groups. CYP3A5*1 expression in recipients increased tacrolimus required dose by 0.023 at first, 0.022 at third, and 0.012 mg/kg/day at sixth month. Its expression in graft tissue increased tacrolimus required dose by 0.024 at first, 0.035 at third, and 0.032 mg/kg/day at sixth month. Considering CYP3A5*1 polymorphism can be helpful in individualization of tacrolimus efficient dose prior to administration, and it can remove initial high-risk lag time (over/underdose period before reaching target blood level) at first few days post-transplantation.

Effect of CYP3A5 polymorphism on liver function and tacrolimus pharmacokinetics after conversion to a once-daily tacrolimus formulation in stable liver transplant patients

“…[6][7][8]14 CYP3A5 expressors carry the *1 variant which encodes the functional enzyme responsible for the metabolism of tacrolimus; therefore, they may require a higher dose of tacrolimus than the non-expressors to achieve the target trough level of the drug. [3][4][5] Our present study demonstrated that CYP3A5 polymorphism influenced both tacrolimus dose and trough level of the drug; the median dose of tacrolimus both before and after switching to the once-daily extended-release formulation was significantly higher in the expressor group than in the non-expressors. This observation is also consistent with the results of previous studies in which CYP3A5 expressors, both adult and pediatric patients, required higher doses of tacrolimus due to higher oral clearance of the drug.…”

“…CYP3A5 genotype is known to play a role in determining the effect of interacting drugs, such as fluconazole, on tacrolimus pharmacokinetics. 5 However, it needs to be stressed that our study did not analyze the issue of drug interaction, and all patients who received agents that might potentially interact with tacrolimus were excluded from the analysis.…”

“…4 Polymorphism at a cryptic splice site may result in either the presence (expressor, *1/*1 and *1/*3 ) or absence (non-expressor, *3/*3 ) ofCYP3A5. 4 The frequencies of CYP3A5 polymorphism differ depending on race, 4,5 with the CYP3A5 expressors (i.e., *1/*1 or *1/*3 ) and MDR1 C3435T wild-type C allele carriers (i.e., CC or CT ) being more prevalent among Asians (51% and 62.1%, respectively) than in Caucasians (10% and 43.4%, respectively). 6 Several studies demonstrated that the expression of CYP3A5 results in a lower tacrolimus exposure, and hence, CYP3A5 expressors might require a higher dose of the drug than non-expressors.…”

The impact of liver transplant recipient and donor genetic variability on tacrolimus exposure and transplant outcome

“…Polymorphisms that alter activity of both CYP3A5 and P‐gp in different tissues, notably the donor liver, recipient gastrointestinal tract and recipient lymphocytes could contribute to rejection and toxicity. Indeed, a recent meta‐analysis has shown that both recipient's and donor's CYP3A5 expression similarly influence tacrolimus concentrations following liver transplant . In contrast, observations relating ABCB1 genetic variability with tacrolimus concentrations remain discordant …”

“…Indeed, a recent meta-analysis has shown that both recipient's and donor's CYP3A5 expression similarly influence tacrolimus concentrations following liver transplant. 6 In contrast, observations relating ABCB1 genetic variability with tacrolimus concentrations remain discordant. 2 In addition to metabolism and transport of tacrolimus, the impact of innate immune responses and cytokine expression also play an important role in transplantation through modification of CYP3A and P-gp expression and/or activity.…”