Abstract
Tacrolimus exhibits high inter-patient pharmacokinetics (PK) variability, as well as a narrow therapeutic index, and therefore requires therapeutic drug monitoring. Germline mutations in cytochrome P450 isoforms 4 and 5 genes (CYP3A4/5) and the ATP-binding cassette B1 gene (ABCB1) may contribute to interindividual tacrolimus PK variability, which may impact clinical outcomes among allogeneic hematopoietic stem cell transplantation (HSCT) patients. In this study, 252 adult patients who received tacrolimus for acute graft versus host disease (aGVHD) prophylaxis after allogeneic HSCT were genotyped to evaluate if germline genetic variants associated with tacrolimus PK and pharmacodynamic (PD) variability. Significant associations were detected between germline variants in CYP3A4/5 and ABCB1 and PK endpoints (e.g., median steady-state tacrolimus concentrations and time to goal tacrolimus concentration). However, significant associations were not observed between CYP3A4/5 or ABCB1 germline variants and PD endpoints (e.g., aGVHD and treatment-emergent nephrotoxicity). Decreased age and CYP3A5*1/*1 genotype were independently associated with subtherapeutic tacrolimus trough concentrations while CYP3A5*1*3 or CYP3A5*3/*3 genotypes, myeloablative allogeneic HSCT conditioning regimen (MAC) and increased weight were independently associated with supratherapeutic tacrolimus trough concentrations. Future lines of prospective research inquiry are warranted to use both germline genetic and clinical data to develop precision dosing tools that will optimize both tacrolimus dosing and clinical outcomes among adult HSCT patients.
Highlights
Allogeneic hematopoietic stem cell transplantation (HSCT) is a widely available and curative treatment option for patients with both malignant and non-malignant hematologic diseases [1,2]
The analysis of germline genetic variants in CYP3A4/5 and ATP-binding cassette B1 gene (ABCB1) is clinically relevant because it has the potential to aid in the optimization of tacrolimus dosing for allogeneic HSCT patients
CYP3A5*3 has been the most extensively studied germline variant known to impact tacrolimus metabolism, and a recently published Clinical Pharmacogenetics Implementatio3nofC2o0 nsortium (CPIC) guideline recognized the role of this single nucleotide polymorphism (SNP) in tacrolimus PK/PD [24]
Summary
Allogeneic hematopoietic stem cell transplantation (HSCT) is a widely available and curative treatment option for patients with both malignant and non-malignant hematologic diseases [1,2]. While the associations between the median steady-state trough concentrations for days +1–3 and the CYP3A4*1b genotype remained significant after adjusting for multiple comparisons (p < 0.01), the associations of days +4–6 median trough concentrations and the CYP3A4*1b genotype did not (p > 0.05; Figure 3B and Table 3) Both CYP3A4*1/*1 patients and patients who harbored at least one CYP3A4*22 allele reached target tacrolimus trough concentrations between days +1 and 3. For ABCB1 C2677T, patients with the C/C genotype had significantly lower target tacrolimus trough concentrations between days +10 and +12 (Figure 3E and Table 3) This association was no longer significant after adjusting for multiple comparisons (p > 0.05). There were no significant associations observed between CYP3A4/5 and ABCB1 SNPs and time to all-grade aGVHD (p > 0.05; Supplementary Figure S1)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
