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

Table 1 Effect of CYP3A4*1B single nucleotide polymorphism on tacrolimus pharmacokinetics

Ref.	Study population	Transplant type/analysis of recipients, donors or both	Findings
Cho et al[84]	70 Korean	Kidney recipients	No association between CYP3A4*1B genotype and tacrolimus dose requirements up to 6 mo after transplantation
Roy et al[85]	38 Caucasian,4 Black,2 Asian	Kidney recipients	No correlation between the CYP3A4*1B SNP and tacrolimus pharmacokinetic at first week and third month after transplantation
Hesselink et al[67]	37 Caucasian,9 Black,18 Asian	Kidney recipients	CYP3A4*1B allele carriers had lower tacrolimus dose-adjusted trough levels with respect to patients carrying the wild-type (*1/*1) genotype at third and 12th month after transplantationThis effect was not observed when analyzing only the Caucasian population.
Hesselink et al[87]	120 Caucasian, 7 Black,8 Asian,1 other	Kidney recipients	No significant correlation observed between CYP3A4*1B SNP and tacrolimus pharmacokinetics when CYP3A5 and ABCB1 SNPs were taken into account
Gervasini et al[33]	103 Spanish	Kidney recipients	Carriers of the CYP3A4*1B variant allele had 59% lower tacrolimus concentrations than those with CYP3A4*1/*1 wild type genotypeAll CYP3A4*1B carriers were also carriers of CYP3A5*1 allele (linkage disequilibrium)

Table 2 Effect of CYP3A5*3 single nucleotide polymorphism on tacrolimus pharmacokinetics

Ref.	Study population	Transplant type/analysis of recipients, donors or both	Findings
Barrera-Pulido et al[94]	53 Caucasian	Liver recipients and donors	CYP3A5*1/*3 recipients with *1/*3 donor livers had lower than minimum required blood tacrolimus levels at 1 mo after transplantation*3/*3 recipients with *1/*3 donors had significantly greater tacrolimus dose requirements at 1 and 2 mo after transplantation
Chakkera et al[95]	24 native American and Caucasian control group	Kidney recipients	Native Americans had lower tacrolimus dose requirements than Caucasians at 1 mo after transplantationNative Americans more commonly expressed CYP3A5*3/*3No difference in blood trough levels or nephropathy between the two groups
Provenzani et al[91]	32 Caucasian	Liver recipients and donors	Dose requirements significantly higher in the case of donors with the CYP3A5*1 allele at 1, 3 and 6 mo after transplantationNo statistically significant difference in dose requirements considering recipient’s genotypes
Provenzani et al[92]	101 Caucasian	Kidney (n = 50, recipients) and liver (n = 51, recipients and donors)	CYP3A5*1 allele in liver donors (n = 51) had a significant effect of decrease on tacrolimus dose-adjusted trough levels at 1, 3 and 6 mo after transplantation. No statistically significant difference in dose requirements considering recipient’s genotypeTacrolimus dose in kidney recipients (n = 50) with CYP3A5*3/*3 genotype was significantly lower than in patients with at least one copy of the wild type allele
Cho et al[84]	70 Korean	Kidney recipients	Those patients who had CYP3A5*1/*3 or *1/*1 genotypes had 80% higher tacrolimus dose requirements than patients homozygotes for *3 allele (up to 6 mo after transplantation)
Glowacki et al[96]	209 French	Kidney recipients	Patients with at least one copy of the CYP3A5*1 allele had significantly higher dose requirements and lower blood trough levels than patients homozygous for the *3 alleleNo influence of this SNP on rejection or graft dysfunction rates.
Goto et al[63]	181 Japanese	Liver recipients and donors	Patients with the CYP3A5*3/*3 genotype had reduced levels of CYP3A5 mRNADose-adjusted tacrolimus trough levels decreased in patients receiving a liver with the *1/*1 genotype
Wei-Lin et al[88]	50 Chinese	Liver recipients and donors	Those patients receiving a liver with the *3/*3 genotype had, at first month after transplantation, significantly higher tacrolimus dose-adjusted trough levels than those with at least one copy of the *1 allele
López-Montenegro Soria et al[97]	35 Spanish	Kidney recipients	Concentration/dose ratios were remarkably lower in patients with at least one copy of the *1 allele than in patients homozygous for the *3 allele
Shi et al[66]	216 Chinese	Liver recipients	Recipients with *1/*1 genotype had higher dosage requirements than those with *3/*3 genotypeThe study suggested also that CYP3A5 enzymatic activity is increased proportionally by the presence of the *1 allele
Jun et al[98]	568 Korean	Kidney and liver recipients (n = 506), and liver donors (n = 62)	Patients with the *3 alleles had higher tacrolimus dose-adjusted trough levels than patients with the *1 allele*1/*1 patients may be more rapid metabolizers than *1 heterozygous patients
Elens et al[99]	150 Belgian	Liver donors	Those patients with at least one *1 allele had at least 67% higher tacrolimus dose requirementsNo influence of CYP3A5 expression on tacrolimus hepatic concentrations
Macphee et al[100]	119 White,23 Black,26 South Asian,12 Middle Eastern	Kidney recipients	Patients with at least one copy of the wild-type *1 allele achieved twofold lower dose-normalized tacrolimus blood concentrations compared with CYP3A5*3/*3 homozygote patients
Thervet et al[101]	168 Caucasian, 8 Black, 12 other	Kidney recipients	Pre-transplant dose adaptation, according to CYP3A5 genotype, is associated with improved achievement of the target blood trough levels
Spierings et al[102]	81 Caucasian, 12 Black, 20 South Asian, 5 other	Kidney recipients	Tacrolimus dose requirements were significantly higher in patients expressing the wild type CYP3A5 genotypeIntra-patient variability of tacrolimus clearance was not associated with the same genotype
Chen et al[103]	120 Chinese	Kidney recipients	CYP3A5 expressers not receiving diltiazem required significantly higher tacrolimus doses than those who received the CYP inhibitor. In non-expressers, no significant difference in tacrolimus dose requirements was observed between the subjects treated with diltiazem and those who were not

Table 3 Effect of ABCB1 single nucleotide polymorphism on tacrolimus pharmacokinetics

Ref.	Study population	Transplant type/analysis of recipients, donors or both	Findings
Provenzani et al[91]	32 Caucasian	Liver recipients and donors	No influence of 3435C>T and 2677G>T SNPs on tacrolimus dose requirements
Cho et al[84]	70 Korean	Kidney recipients	No association between ABCB1 genotype and tacrolimus dose requirements
Shi et al[66]	216 Chinese	Liver recipients	No association between any ABCB1 SNPs and tacrolimus dose requirements or blood trough levels
Jun et al[98]	568 Korean	Kidney and liver recipients (n = 506), and liver donors (n = 62)	No correlation between ABCB1 genotype and tacrolimus dose-adjusted blood trough levels
Gervasini et al[33]	103 Spanish	Kidney recipients	None of the ABCB1 polymorphisms were associated with changes in dose-adjusted blood trough levels and in dose requirementsNo association between ABCB1 genotype and tacrolimus-induced toxicity
Kuypers et al[104]	304 Belgian	Kidney recipients	No significant impact of ABCB1 genotype on tacrolimus exposure parameters or dosing requirements
Provenzani et al[92]	101 Caucasian	Kidney (n = 50) and liver (n = 51, recipients and donors)	No ABCB1 influence on dosing in liver transplant patientsThose patients receiving kidney transplant carrying the 2677T/A allele required significantly higher doses than those patients with the wild type allele
Goto et al[63]	181 Japanese	Liver recipients and donors	In the first week after transplantation, the recipients with wild type ABCB1 allele had lower tacrolimus dose-adjusted blood trough levelsNo difference observed after 2 wk
Herrero et al[43]	71 Spanish	Kidney recipients	Patients with wild type ABCB1 alleles had more stable tacrolimus concentrations within the therapeutic range during the first 3 moOn the contrary, patients carrying the polymorphic ABCB1 alleles showed a mean increase in tacrolimus blood concentration of more than 60%
Wei-Lin et al[88]	50 Chinese	Liver recipients and donors	Recipients with the wild type ABCB1-3435CC allele had significantly higher tacrolimus dose requirements than those with C3435T at 1 and 2 wk and 1 mo after transplantation
López-Montenegro Soria et al[97]	35 Spanish	Kidney recipients	Wild type ABCB1 3435CC patients had 40% lower concentration/dose ratios than those patients with variant alleles
Elens et al[99]	150 Belgian	Liver donors	ABCB1 genetic polymorphisms significantly influence tacrolimus hepatic concentrations, but have no effect on tacrolimus blood levelsPatients with ABCB1 1236C>T polymorphism showed significantly better liver functions and lower Banff scores with respect to patients with the wild-type allele

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