The impact of CYP3A5, NR1I2, and POR polymorphisms on tacrolimus dose-adjusted concentration and clinical outcomes in adult allogeneic hematopoietic stem cell transplantation.

Abstract

1. Polymorphisms in genes related to drug-metabolizing genes may affect tacrolimus exposure. This study aimed to assess the influence of CYP3A5, NR1I2, and POR polymorphisms on tacrolimus pharmacokinetics and outcomes in allogeneic hematopoietic stem cell transplantation (HSCT).2. 46 adult patients receiving oral tacrolimus at an initial dose of 0.03mg/kg/day for acute graft versus host disease (GVHD) prophylaxis after allogeneic HSCT were enrolled in this retrospective study. Genetic polymorphisms were detected in relation to concentration/dose (C/D) ratios of tacrolimus and the incidence of acute GVHD and acute kidney injury (AKI).3. The CYP3A5 *3/*3 genotype and co-administration of voriconazole were significantly associated with increased C/D ratios of tacrolimus (P < 0.05). NR1I2 8055CC present a significant higher tacrolimus C/D ratio compared with carriers of 8055CT and 8055TT genotypes in allogeneic HSCT recipients with the CYP3A5*1 allele (P = 0.033). Younger age and recipients with the CYP3A5*1 allele were significantly associated with higher incidence of II-IV acute GVHD post-transplantation.4. CYP3A5*3, NR1I2 8055 C > T, and concomitant use of voriconazole are important determinants affecting tacrolimus pharmacokinetics. Moreover, CYP3A5*1 allele and younger age are independent risk factors for II-IV acute GVHD in HSCT recipients.