Abstract
A polymorphism in the gene encoding the metabolic enzyme cytochrome P450 family 3 subfamily A member 5 (CYP3A5) is a particularly influential factor in the use of tacrolimus in Japanese patients. Those who are homozygotic for the *3 mutation lack CYP3A5 activity, which results in substantial individual differences in tacrolimus metabolism. The aim of this study was to analyze the relationship between individual differences in tacrolimus blood concentration changes and CYP3A5 polymorphisms in allogeneic hematopoietic stem cell transplantation recipients during the period of increasing blood concentration of the drug following treatment onset. This was a prospective observational cohort study, involving 20 patients administered tacrolimus by continuous infusion. The subjects were divided into the *1/*3 and *3/*3 groups based on CYP3A5 polymorphism analysis. The tacrolimus blood concentration/dose (C/D) ratio increased from day 1 and was largely stable on day 5, and a significant difference was observed between the *1/*3 and *3/*3 groups in the time course of the C/D ratio during this period (p < 0.05). This study reveals the effects of CYP3A5 polymorphism on continuous changes in tacrolimus blood concentration.
Highlights
Tacrolimus is a macrolide immunosuppressant, and its immunosuppressive activity is mediated by complexes formed with FKBP prolyl isomerase 1A, which binds to calcineurin and inhibits its activity [1,2]
This study revealed the effects of CYP3A5 polymorphism on the continuous changes in tacrolimus blood concentration with high accuracy for the first time
This study demonstrated the important relationship between CYP3A5 polymorphism and tacrolimus pharmacokinetics in hematopoietic stem cell transplantation (HSCT) recipients, which will be especially useful when establishing initial doses
Summary
Tacrolimus is a macrolide immunosuppressant, and its immunosuppressive activity is mediated by complexes formed with FKBP prolyl isomerase 1A, which binds to calcineurin and inhibits its activity [1,2]. Tacrolimus is a prophylactic for post-transplant organ rejection and graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (HSCT), and a therapy for autoimmune disease. A correlation between blood tacrolimus concentration and its clinical efficacy and toxicity as a GVHD prophylactic has been reported [3]. The therapeutic range of the blood tacrolimus concentration is narrow, and tacrolimus pharmacokinetics are highly variable among individuals [4,5]. Whole blood is commonly used to assess therapeutic tacrolimus concentrations, as tacrolimus is distributed mainly in red blood cells (RBCs) [6,7]. We examined this characteristic of tacrolimus and reported that differences in RBC distribution
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