Abstract
Cytochrome P450 (CYP) 3A5 polymorphism influences tacrolimus metabolism, but its effect on the drug pharmacokinetics in liver transplant recipients switched to once-daily extended-release formulation remains unknown. The aim of this study is to analyze the effect of CYP3A5 polymorphism on liver function after once-daily tacrolimus conversion in liver transplant patients. A prospective open-label study included 60 stable liver transplant recipients who underwent 1:1 conversion from twice-daily tacrolimus to once-daily tacrolimus. All participants were genotyped for CYP3A5 polymorphism. The study was registered at ClinicalTrials.gov (NCT 02882113). Twenty-eight patients were enrolled in the CYP3A5 expressor group and 32 in the non-expressor group. Although there was no statistical difference, incidence of liver dysfunction was higher in the expressor group than in the non-expressor group when converted to once-daily extended-release tacrolimus (p = 0.088). No biopsy-proven acute rejection, graft failure, and mortality were observed in either group. The decrease in dose-adjusted trough level (−42.9% vs. −26.1%) and dose/kg-adjusted trough level of tacrolimus (−40.0% vs. −23.7%) was significantly greater in the expressor group than in the non-expressors after the conversion. A pharmacokinetic analysis was performed in 10 patients and tacrolimus absorption in the non-expressor group was slower than in the expressor group. In line with this observation, the area under the curve for once-daily tacrolimus correlated with trough level (Cmin) in the non-expressors and peak concentration (Cmax) in the expressors. CYP3A5 genotyping in liver transplant recipients leads to prediction of pharmacokinetics after switching from a twice-daily regimen to a once-daily dosage form, which makes it possible to establish an appropriate dose of tacrolimus.
Highlights
Tacrolimus is an effective immunosuppressant, and its use in liver transplantation (LT) is well established [1]
The intra- and interindividual variability in tacrolimus pharmacokinetics and pharmacodynamics is partly associated with the polymorphism of the genes for cytochrome P450 enzymes, CYP3A4 and CYP3A5, and the efflux transporter P-glycoprotein (P-gp); all these molecules have been implicated in altered absorption and metabolism of tacrolimus [4]
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
Summary
Tacrolimus is an effective immunosuppressant, and its use in liver transplantation (LT) is well established [1]. The drug has a narrow therapeutic window, and its pharmacokinetics and pharmacodynamics vary considerably at both intraindividual and interindividual levels; establishing an empirical dosage regimen may pose a challenge [2,3,4]. Given a poor correlation between the dosage of tacrolimus and its blood concentration, the dose is often adjusted based on the latter parameter to achieve an optimal balance between the efficacy and toxicity of the drug. The intra- and interindividual variability in tacrolimus pharmacokinetics and pharmacodynamics is partly associated with the polymorphism of the genes for cytochrome P450 enzymes, CYP3A4 and CYP3A5, and the efflux transporter P-glycoprotein (P-gp); all these molecules have been implicated in altered absorption and metabolism of tacrolimus [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]
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