Effects of Genotype on Tacrolimus Pharmacokinetics and Graft-versus-Host Disease Incidence in Allogeneic Hematopoietic Stem Cell Transplantation.

Tacrolimus (Tac) is pivotal in preventing acute graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (alloHSCT). It has been reported that genetic factors, including * and 22 polymorphisms, have an impact on Tac metabolism, dose requirement, and response to Tac. There is limited information regarding this topic in alloHSCT. The genotype and a low Tac trough concentration/dose ratio (Tac C/D ratio) can be used to identify fast metabolizers and predict the required Tac dose to achieve target concentrations earlier. We examined 62 Caucasian alloHSCT recipients with a fast metabolizer phenotype (C/dose ratio ≤ 1.5 ng/mL/mg), assessing genotypes and acute GVHD incidence. Forty-nine patients (79%) were poor metabolizers (2 copies of the variant *3 allele) and 13 (21%) were CYP3A5 expressers ( or genotypes). CYP3A5 expressers had lower C at 48 h (3.7 vs. 6.2 ng/mL, = 0.03) and at 7 days (8.6 vs. 11.4 ng/mL, = 0.04) after Tac initiation, tended to take longer to reach Tac therapeutic range (11.8 vs. 8.9 days, = 0.16), and had higher incidence of both global (92.3% vs. 38.8%, < 0.001) and grade II-IV acute GVHD (61.5% vs. 24.5%, = 0.008). These results support the adoption of preemptive pharmacogenetic testing to better predict individual Tac initial dose, helping to achieve the therapeutic range and reducing the risk of acute GVHD earlier.