Pharmacogenetic considerations for optimizing tacrolimus dosing in liver and kidney transplant patients

Table 4 Effect of various single nucleotide polymorphisms on tacrolimus pharmacodynamics

Ref.	Study population	Transplant type/analysis of recipients, donors or both	Findings
Jun et al[98]	568 Korean	Kidney and liver recipients (n = 506), and liver donors (n = 62)	No difference in incidence of organ rejection between different genotypes
Chen et al[103]	120 Chinese	Kidney recipients	Patients that received genotype-guided initial tacrolimus dosing vs standard protocol dose were more likely to achieve target drug levelsNo influence on incidence of adverse effects between CYP3A5 expressers and non-expressers
Jacobson et al[105]	945 (different ethnicities)	Kidney recipients	Every increase in tacrolimus blood trough level of 1 ng/mL increased the risk of early tacrolimus nephrotoxicity by 22%Polymorphism was not associated with an increased or decreased risk of tacrolimus-related nephrotoxicity
Kuypers et al[106]	273 White,3 Hispanic,24 North African,2 African,2 Asian	Kidney recipients	Delayed graft function was associated with higher initial mean tacrolimus blood trough levels and lower tacrolimus daily dose requirements, especially in CYP3A5 non-expressersCYP3A5 expressers may be at lower risk of new-onset diabetes after transplant (NODAT) due to diminished exposure to potentially toxic tacrolimus levels
Kuypers et al[104]	273 White,3 Hispanic,24 North African,2 African,2 Asian	Kidney recipients	Patients expressing the CYP3A5*1 allele and a functional CYP3A5 enzyme may be predisposed to developing calcineurin-inhibitor-associated nephrotoxicity (CNIT) following transplantation due to greater daily tacrolimus dose requirementsThis was observed especially in patients continuing corticosteroid therapy The incidence of delayed graft function and post-transplant diabetes mellitus was not different between CYP3A5 expressers and non-expressers
Chen et al[107]	319 Hispanic	Kidney recipients	SNPs in the cytoplasmic NFATc4 gene may confer a certain protection or also predisposition for NODAT. Patients carrying the T allele and the T-T-T-T-G haplotype showed a trend of protection from NODAT while patients with the C-C-C-G-G haplotype were associated with an increased risk of NODATThe use of sirolimus and tacrolimus and advanced age were also possibly correlated in development of NODAT
Cho et al[84]	70 Korean	Kidney recipients	Higher drug-related toxicity in patients with the CYP3A5*1 allele than in those with the CYP3A5*3 SNPNo difference in graft survival between the two genotypes
Barrera-Pulido et al[94]	53 Spanish	Liver recipients and donors	Patients with CYP3A5*3/*3 allele receiving livers with an ABCB1 SNP had lower frequency of renal dysfunction, same rejection rate and higher diabetes rate
Shi et al[66]	216 Chinese	Liver recipients	Patients with the CPY3A5*3 allele had greater risk of early renal injury than the patients with the *1 allele