The Effect of CYP3A4 Polymorphisms on Tacrolimus Clinical Pharmacology and Clinical Outcomes Among UNC Allogeneic Hematopoietic Stem Cell Transplant Patients

Introduction: Acute Graft vs Host Disease (aGVHD) is a life-threatening, T-cell mediated immune reaction that may occur in allogeneic hematopoietic stem cell transplant (HSCT) patients. Tacrolimus is the cornerstone of aGVHD prophylaxis regimens for allogeneic HSCT patients, however it is a narrow therapeutic index drug. Tacrolimus is primarily metabolized through the CYP3A4 and CYP3A5 enzymes in the liver, and its concentrations could be impacted by two polymorphisms in CYP3A4 (CYP3A4*22, CYP3A4*1b) which may in turn impact onset and severity of aGVHD in allogeneic HSCT patients. Currently, the effect of these SNPs on tacrolimus trough concentrations and incidence and severity of aGVHD in allogeneic HSCT patients is unknown. The primary objective of this pharmacogenetics research study was to determine whether genetic variations in CYP3A4 influence steady-state tacrolimus concentrations, and are associated with risk of developing aGVHD in allogeneic HSCT patients.Methods: This is an observational, retrospective study where we analyzed 274 BMT patients who received their first allogeneic HSCT at the UNC health systems and received oral tacrolimus for aGVHD prophylaxis from January 2011 to May 2016 were identified through the UNC BMT database and 253 were retrospectively analyzed for incidence and severity of aGVHD. Genotyping for CYP3A4*22 and CYP3A4*1b was performed using TaqMan assays and RT-PCR on DNA collected for HLA-matching prior to transplant. Multivariate analyses will be performedResults: There was an approximate 60:40 ratio of males to females, and a 12% Black population represented in this study. Patients with two copies of the CYP3A4*1b variant allele (the CC homozygous genotype) had lower mean tacrolimus trough concentrations (4.06+2.06) than patients with the TT homozygous genotype (6.82+0.64, P=0.009). Patients with the CT genotype had lower tacrolimus trough concentrations than those with the TT genotype (3.9+0.95 vs 6.82+0.95, P=0.14). For CYP3A4*22, patients with the AA or AG genotypes experienced higher tacrolimus trough concentrations (8.43+2.54) than patients with the GG genotype (6.3+0.59, P=0.14). Of the 253 patients analyzed, 116 patients experienced some manifestations of aGVHD and the most commonly targeted organ amongst them was the skin (68.9%). The second most targeted organ was the gastrointestinal tract (30.3%) and hepatic aGVHD was observed least frequently (0.8%).Conclusions: Patients with the CC or CT genotype for CYP3A4*1b experienced significantly lower tacrolimus trough concentrations than patients with the TT genotype. Patients with the AA or AG CYP3A4*22 genotypes experienced lower tacrolimus trough concentrations than patients with GG genotype, however this was not significant. There were no significant associations observed between CYP3A4*1b or CYP3A4*22 and incidence and severity of aGVHD. This is a preliminary study intended to generate data that can be applied to future population pharmacokinetic studies to tacrolimus dosing strategies based on genotype. Although there were no significant associations noted with aGVHD, this may be attributable to many clinical factors that could not be accounted for due to the retrospective design and these data need to be further analyzed using multivariate analyses to account for as many of these factors as possible.Doctor of Pharmac