Effect of CYP3A4, CYP3A5, and ABCB1 Polymorphisms on Intravenous Tacrolimus Exposure and Adverse Events in Adult Allogeneic Stem Cell Transplant Patients

Abstract

A B S T R A C T Pharmacogenetics influences oral tacrolimus exposure; however, little data exist regarding i.v. tacrolimus. We investigated the impact of genetic polymorphisms in CYP3A4, CYP3A5, and ABCB1 on i.v. tacrolimus exposure and toxicity in adult patients receiving an allogeneic hematopoietic stem cell transplant for hematologic malignancies. Germline DNA was extracted from buccal swabs and genotyped for CYP3A4, CYP3A5, and ABCB1 polymorphisms. Continuous i.v. infusion of tacrolimus .03 mg/kg/day was initiated on day +5 post-transplant, and steady-state blood concentrations were measured 4 days later. We evaluated the association between phenotypes and prevalence of nontherapeutic target concentrations (below or above 5 to 15 ng/mL) as well as tacrolimus-related toxicities. Of 63 patients, 28.6% achieved the target concentration; 71.4% were >15 ng/mL, which was more common in CYP3A4 intermediate/normal metabolizers (compared with rapid) and those with at least 1 ABCB1 C2677T loss-of-function allele (P < .05). ABCB1 C2677T was significantly associated with concentrations >15 ng/mL (odds ratio, 6.2; 95% confidence interval, 1.8 to 23.6; P = .004) and tacrolimus-related toxicities (odds ratio, 7.5; 95% confidence interval, 1.6 to 55.2; P = .02). ABCB1 C2677T and CYP3A4 are important determinants of i.v. tacrolimus exposure, whereas ABCB1 C2677T also impacts tacrolimus-related toxicities in stem cell transplants.

Influence of Germline Genetics on Tacrolimus Pharmacokinetics and Pharmacodynamics in Allogeneic Hematopoietic Stem Cell Transplant Patients

“…Achieving the tacrolimus target trough is important to reduce nephrotoxicity resulting from supratherapeutic tacrolimus concentrations. Three loss-of-function germline variants located in the exonic regions of ABCB1 (rs1128503, C1236T; rs2032582, C2677T; rs1045642, C3435T) have been implicated in both inter-patient tacrolimus PK variability and treatment-emergent toxicities [30][31][32]. In our study, AKI was not significantly associated with any of the ABCB1 or CYP3A4/5 SNPs.…”

“…ABCB1 encodes P-gp, and it is highly expressed in both the enterocytes and hepatocytes, and thus ABCB1 SNPs could explain interindividual tacrolimus absorption and exposure [29]. However, P-gp is also located on the apical membrane of renal tubular epithelial cells, and SNPs have been associated with increased risk of tacrolimus-induced nephrotoxicity [30][31][32].…”

“…These recommendations come from experience in solid organ transplant patients, and there is a lack of evidence in the allogeneic HSCT patient population to apply the CPIC recommendations. While recent publications have begun to address CYP3A4/5-guided tacrolimus dosing in allogeneic HSCT, these pharmacogenetic studies have either focused on intravenous administration of tacrolimus [30], or underrepresented black patients in the studies [11,33,34]. Importantly, the CYP3A5*3 variant minor allele frequency (MAF) varies across races, and is estimated to be as high as 95% among white patients but only approximately 33% in black patients [35].…”

Evaluation of the performance of a prior tacrolimus population pharmacokinetic kidney transplant model among adult allogeneic hematopoietic stem cell transplant patients

“…Germline genetic variations in genes that encode for proteins central to tacrolimus metabolism and transport are associated with interindividual tacrolimus in PK/PD variability in both the solid organ and the HCT patient populations 9–11 . CYP3A5 has been identified as a gene with functional variants known to alter tacrolimus PK in seminal guidelines from the Clinical Pharmacogenetics Implementation Consortium and the Dutch Pharmacogenetics Working Group 12,13 .…”

Association of cytotoxic T-lymphocyte antigen-4 (CTLA-4) single nucleotide polymorphism in donors with clinical outcome after allogeneic hematopoietic stem cell transplantation: a meta-analysis

“…Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative therapy for several hematological malignancies and nonmalignant diseases, because of its substantial morbidity and mortality, posttransplant survival, relapse and the occurrence of GVHD are issues concerned by both clinicians and researchers. Although varieties of studies [1][2][3][4] have reported the potential relationship of single nucleotide polymorphisms (SNPs) in genes encoding minor histocompatibility antigens, cytokine, chemokines and even drug-metabolizing enzymes with transplant outcomes, there are currently no well-established predicted biomarkers of clinical results after allo-HSCT. Therefore, investigations aiming to explore the pretransplantation predictors of genetic variants to assist in the risk assessment of adverse outcomes is critical, which can provide potential targets for novel prevention and treatment strategies.…”