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

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