Impact of CYP3A5, POR, and CYP2C19 Polymorphisms on Trough Concentration to Dose Ratio of Tacrolimus in Allogeneic Hematopoietic Stem Cell Transplantation.

Kimitaka Suetsugu,Yasuo Mori,Tomohiro Shigematsu,Nobuaki Egashira,Toshihiro Miyamoto,Satohiro Masuda,Nanae Yamamoto,Koichi Akashi

doi:10.3390/ijms20102413

Abstract

Single nucleotide polymorphisms in drug-metabolizing genes may affect tacrolimus pharmacokinetics. Here, we investigated the influence of genotypes of CYP3A5, CYP2C19, and POR on the concentration/dose (C/D) ratio of tacrolimus and episodes of acute graft-versus-host disease (GVHD) in Japanese recipients of allogeneic hematopoietic stem cell transplantation (HSCT). Thirty-six patients receiving the first HSCT using tacrolimus-based GVHD prophylaxis were enrolled with written informed consent. During continuous intravenous infusion, HSCT recipients carrying the CYP3A5*1 allele, particularly those with at least one POR*28 allele, had a significantly lower tacrolimus C/D ratio throughout all three post-HSCT weeks compared to that in recipients with POR*1/*1 (p < 0.05). The CYP3A5*3/*3 genotype and the concomitant use of voriconazole were independent predictors of an increased tacrolimus C/D ratio during the switch from continuous intravenous infusion to oral administration (p < 0.05). In recipients receiving concomitant administration of voriconazole, our results suggest an impact of not only CYP3A5 and CYP2C19 genotypes, but also plasma voriconazole concentration. Although switching from intravenous to oral administration at a ratio of 1:5 was seemingly appropriate in recipients with CYP3A5*1, a lower conversion ratio (1:2–3) was appropriate in recipients with CYP3A5*3/*3. Our results suggest that CYP3A5, POR, and CYP2C19 polymorphisms are useful biomarkers for individualized dosage adjustment of tacrolimus in HSCT recipients.

Highlights

Tacrolimus has been widely used as an immunosuppressive drug for prophylaxis of graft-versus-host disease (GVHD) after allogenic hematopoietic stem cell transplantation (HSCT) [1,2,3,4,5,6]
We examined the effect of gene polymorphisms on the pharmacokinetics of tacrolimus during the early stage of continuous intravenous infusion and when switching from continuous intravenous infusion to oral administration in HSCT recipients
There were no significant differences between the two groups with respect to age, sex, body weight, P450 oxidoreductase (POR) genotype, CYP2C19 genotype, diagnosis, donor type, stem cell source, human leukocyte antigen (HLA) disparity, conditioning regimen, GVHD prophylaxis, concomitant antifungal agents, or levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin (T-Bil), or serum creatinine (Scr)

Summary

Introduction

Tacrolimus has been widely used as an immunosuppressive drug for prophylaxis of graft-versus-host disease (GVHD) after allogenic hematopoietic stem cell transplantation (HSCT) [1,2,3,4,5,6]. The POR*28 SNP varies in frequency: 36% in Chinese-Americans, 26.4% in Caucasians, 19.1% in African-Americans, and 31% in Mexicans [25] Those with the CYP3A5*1 allele carrying one or two POR*28 alleles (*1/*28 and *28/*28 genotypes) have lower tacrolimus C/D ratios and higher tacrolimus dose requirements than those with the CYP3A5*1 allele without POR*28 (*1/*1 genotype) among kidney transplant recipients [26]. It is still unclear whether the POR*28 polymorphism affects the pharmacokinetics of tacrolimus in HSCT recipients, as there are no reports describing this in HSCT. We focused on the CYP3A5, POR, and CYP2C19 polymorphisms and the interactions of tacrolimus with azole antifungal agents

Patient Background

Patients and Tacrolimus Administration

Statistical Analysis