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

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.

Impacts of High Intra- and Inter-Individual Variability in Tacrolimus Pharmacokinetics and Fast Tacrolimus Metabolism on Outcomes of Solid Organ Transplant Recipients

“…Despite the fact that monitoring blood trough concentrations is an effective method for adjusting tacrolimus oral doses, clinical studies have reported that it may not be valuable for future dosage estimation and may also not be an accurate assessment of overall drug exposure among various individuals [ 17 , 23 , 24 , 25 , 26 ]. It is sometimes challenging to achieve and maintain target tacrolimus trough concentrations despite periodic tacrolimus TDM [ 3 ]. Hence, the determination of the area under the curve (AUC) over a dosing interval is generally considered the best indicator of optimal dosing, though multiple blood samples may be required, which, for practical and financial reasons, limits its clinical utility [ 38 ].…”

“…In the modern era, there has been increasing interest in the identification and validation of genetic variations that contribute to IPV [ 72 , 73 ]. Germline mutations in ATP-binding cassette B1 gene (ABCB1) and CYP3A4/5 probably contribute to interindividual tacrolimus PK variability [ 3 , 17 , 74 ]. Single nucleotide polymorphisms (SNPs) in CYP3A5 could contribute 40%–50% of inter-individual PK variability [ 75 , 76 ].…”

“…Genetic variants in drug transporters may also add to tacrolimus’ PK variability. The ABCB1 gene, immensely expressed on hepatocytes and enterocytes, encodes P-gp; ABCB1 SNPs potentially add to inter-individual tacrolimus absorption and nephrotoxicity, respectively [ 3 ]. Renal tubular epithelial cells express P-gp, and SNPs have been associated with a variable risk of tacrolimus-induced nephrotoxicity [ 39 , 77 ].…”

“…Calcineurin inhibitor (CNI)-based immunosuppression is a regularly used therapeutic regimen in solid organ transplantation (SOT), tacrolimus (also known as FK506) being the front-running CNI [ 1 , 2 ] and mainstay of triple immunosuppressive drug regimens [ 3 ]. Before extended-release formulations became available, tacrolimus was traditionally given twice daily [ 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 ] ( Table 1 ).…”

“…Protein binding is noted to be primarily with α1-acid glycoprotein and albumin [ 16 , 18 ]. Tacrolimus undergoes extensive hepatic metabolism, and less than 1% of the unaltered parent drug is eliminated [ 3 ].…”