The Impact of CYP3A4*22 on Tacrolimus Pharmacokinetics and Outcome in Clinical Practice at a Single Kidney Transplant Center

Abstract

Background: Although there is evidence that the CYP3A4*22 variant should be considered in tacrolimus dosing in renal transplantation, its impact beyond tacrolimus dose requirements remains controversial.Methods: In a cohort of 121 kidney transplant recipients, we analyzed the CYP3A4*1B, CYP3A4*22, and CYP3A5*3 alleles and the ABCB1 variants 1236C>T, 2677G>T/A, and 3435C>T for their impact on exposure and dose requirement. Relevant clinical outcome measures such as acute rejection within the first year after transplantation, delayed graft function, and renal function at discharge (estimated glomerular filtration rate) were evaluated.Results: Extensive metabolizer (n = 17, CYP3A4*1/*1 carriers with at least one CYP3A5*1 allele) showed significantly higher tacrolimus dose requirement (P = 0.004) compared with both intermediate metabolizer (IM, n = 93, CYP3A5*3/*3 plus CYP3A4*1/*1 or CYP3A4*22 carriers plus one CYP3A5*1 allele), and poor metabolizer (n = 11, CYP3A4*22 allele in combination with CYP3A5*3/*3) after onset of therapy. Significantly higher dose requirement was observed in CYP3A5 expressers (P = 0.046) compared with non-expressers again at onset of therapy. Using the log additive genetic model, the area under the curve for the total observation period up to 16 days was significantly associated with the CYP3A5*3 genotype (P = 3.34 × 10-4) as well as with the IM or extensive metabolizer phenotype (P = 1.54 × 10-4), even after adjustment for multiple testing. Heterozygous carriers for CYP3A4*22 showed significantly higher areas under the curve than the CYP3A4*1/*1 genotype in the second week post-transplantation (adjusted P = 0.016). Regarding clinical outcomes, acute rejection was significantly associated with human leukocyte antigen mismatch (≥3 alleles; OR = 12.14, 95% CI 1.76, 525.21, P = 0.019 after correction for multiple testing). Graft recipients from deceased donors showed higher incidende of delayed graft function (OR 7.15, 95% CI 2.23, 30.46, adjusted P = 0.0008) and a lower estimated glomerular filtration rate at discharge (P = 0.0001). Tested CYP3A4 or CYP3A5 variants did not show any effects on clinical outcome parameters. ABCB1 variants did neither impact on pharmacokinetics nor on clinical endpoints.Conclusion: At our transplantation center, both CYP3A5*3 and, to a lesser extent, CYP3A4*22 affect tacrolimus pharmacokinetics early after onset of therapy with consequences for steady-state treatment in routine clinical practice.

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

“…In addition, CYP3A4 is the most abundant cytochrome P450 enzyme in human hepatocytes and is also responsible for tacrolimus metabolism. Two intragenic CYP3A4 SNPs have been hypothesized to contribute to tacrolimus interindividual PK variability [27,28]. In addition to SNPs in genes that encode proteins that influence tacrolimus metabolism, germline variants in drug transporters may also contribute to tacrolimus PK variability.…”

Clinical significance of personalized tacrolimus dosing by adjusting to donor CYP3A‐status in liver transplant recipients

“…Besides the assessment of dose‐requirement, genotyping for CYP3A5 was reported to facilitate rapid dose‐finding and improved achievement of target tacrolimus concentration in kidney transplant patients 39,40 . For refining genotype‐based tacrolimus dosing, CYP3A4*22 resulting in reduced CYP3A4 expression has recently been suggested to be integrated with CYP3A5 genotype information 7,41,42 . Nonetheless, variability in tacrolimus dose‐requirement appears to be far from that is explainable by CYP3A5*1 and CYP3A4*22 (<20%) 43 .…”

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

“…To date, multiple studies have confirmed that in kidney transplant recipients, sub-therapeutic tacrolimus levels or high tacrolimus IPV can result in increased dnDSA formation [ 25 , 65 , 66 , 67 , 68 , 69 , 70 , 71 ]. 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 ]. Two intragenic CYP3A4 SNPs are hypothesized to cause inter-individual PK variability [ 72 , 73 ]. Genetic variants in drug transporters may also add to tacrolimus’ PK variability.…”