Salvadori M, Tsalouchos A. Pharmacogenetics of immunosuppressant drugs: A new aspect for individualized therapy. World J Transplant 2020; 10(5): 90-103 [PMID: 32864355 DOI: 10.5500/wjt.v10.i5.90]
Corresponding Author of This Article
Maurizio Salvadori, MD, Professor, Department of Renal Transplantation, Careggi University Hospital, Viale Pieraccini 18, Florence 50139, Italy. [email protected]
Research Domain of This Article
Transplantation
Article-Type of This Article
Review
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World J Transplant. May 29, 2020; 10(5): 90-103 Published online May 29, 2020. doi: 10.5500/wjt.v10.i5.90
Table 1 Candidate single-nucleotide polymorphisms related to the pharmacodynamics pathways of calcineurin inhibitors with quality of evidence of existing data and level of recommendation[6]
Drugs
Gene
SNP
MAF
QOE
LOR
PPIA
rs8177826, rs6850
G = 0.033, G = 0.384
C, D
3, 4
PPP3CA
rs45441997, rs3804358rs
G = 0.268, G = 0.133
A, A
1, 1
PPP3CB
rs376679
T = 0.066
A
1
PPP3R1
rs3039851, rs1868402
NA, G = 0.301
B, A
2, 1
CALM1
rs12885713
T = 0.400
A
1
CALM3
rs150954567, rs3814843, rs3814843
NA, C = 0.358, C = 0.018
A, C, C
1, 3, 3
IL2
rs2069762, rs2069763, rs6822844
G = 0.232, A = 0.400, T = 0.146
A, B, C
4, 1, 3
Table 2 Summary of tacrolimus genotype directed randomized controlled trials[34,35]
Limitations
Strengths
TAC initiated on day 7 (French); Single SNP studied (CYP3A5*3); Limited genotypic diversity with few CYP3A5*1/1 carriers (French); Used same dose for CYP3A5*1/1 and *1/*3 carriers (French); Genotype-based dosing did not account for clinical factors; Low risk populations and underpowered for AR; Dosing regimens designed to achieve target of 10-15 ng/mL
Established the safety of genotype directed dosing (both trials); Genotype dosing reduced time to therapeutic (French); Genotype dosing had greater proportion of troughs in range at day 3 and 10 (French); Fewer dose adjustments (French)
Table 3 Dosing recommendation for tacrolimus based on CYP3A5 phenotype[12]
CYP3A5 phenotype
Implications for tacrolimus pharmacologic measures
Therapeutic recommendations
Classification of recommendation
Extensive metabolizer (CYP3A5 expresser)
Lower dose-adjusted trough concentrations of TAC and decreased chance of achieving target TAC concentrations
Increase starting dose to 1.5-2 times recommended starting dose. Use therapeutic drug monitoring to guide dose adjustments
Strong
Intermediate metabolizer (CYP3A5 expresser)
Lower dose-adjusted trough concentrations of TAC and decreased chance of achieving target TAC concentrations
Increase starting dose to 1.5-2 times recommended starting dose. Use therapeutic drug monitoring to guide dose adjustments
Strong
Poor metabolizer (CYP3A5 non expresser)
Higher dose-adjusted trough concentrations of TAC and increased chance of achieving target TAC concentrations
Initiate therapy with standard recommended dose. Use therapeutic drug monitoring to guide dose adjustments
Strong
Table 4 Amount of variability in tacrolimus troughs that can be explained in African American model[39]
Table 5 Tacrolimus doses and concentrations by ancestry in the first 6 mo posttransplant[40]
Native American, n = 77
Asian ancestry, n = 91
European ancestry, n = 1966
African American, n = 461
P value
Trough concentration (ng/mL)
8.3
8.4
8.4
6.9
< 0.0001
Total daily dose (mg)
5.0
6.0
5.0
8.0
< 0.0001
Dose-normalized trough concentration (ng/mL per total daily dose in mg)
1.73
1.50
1.56
0.78
0.0001
Table 6 Candidate single-nucleotide polymorphisms related to the pharmacodynamics pathways of mammalian target of rapamycin inhibitors with quality of evidence of existing data and level of recommendation[6]
Drugs
Gene
SNP
MAF
QOE
LOR
mTOR inhibitors
mTOR
rs2024627
T = 0.270
A
1
rs2295080
G = 0.308
A
1
rs1883965
A = 0.288
B
1
rs1057079
G = 0.243
C
3
Table 7 Candidate single-nucleotide polymorphisms related to the pharmacodynamics pathways of mycophenolic acid with quality of evidence of existing data and level of recommendation[6]
Drugs
Gene
SNP
MAF
QOE
LOR
Mycophenolic acid
IMPDH2
rs11706052
G = 0.115
A
1
IMPDG1
rs2278293
A = 0.431
C
4
IMPDH1
rs2278294
A = 0.323
C
4
Table 8 Studies documenting the association between some single-nucleotide polymorphisms and transplant outcomes[67,73,77-79]
Drug
SNPs
Patients (n)
Outcomes
OR
CI
P value
CNI
rs2069762TT
50
CAN
4.57
1.04-20.11
0.044
CNI
rs8177826
290
Nephrotoxicity
3.49
1.47-8.24
0.006
CNI
rs2069762
90
AR
6.3
1.8-22.15
0.005
EC-MPS
rs11706052
237
AR
3.39
1.42-8.09
0.006
EC-MPS
rs2278293
191
AR
0.34
0.15-0.76
0.008
EC-MPS
rs2278294
191
AR
0.40
0.18-0.89
0.02
Table 9 Association of variant ADME genes to pharmacokinetics of selected small molecule immunosuppressants[80]
Drug
Phase I enzymes
Phase II enzymes
Uptake transporters
ABC transporters
CYP3A4
CYP3A5
UGT1A9
OATP1B1/3
ABCB1
ABCC2
IMPDH I/II
rs35599367
rs776746, rs10264272
rs17868320, rs6714486
rs41490556, rs4149117
rs1128503, rs2032582, rs1045642
rs717620
rs2278293, rs2278294, rs11706052
Mycophenolic acid
-
-
+
(+)
-
(+)
+
Cyclosporine
(+)
-
-
-
(+)
-
-
Tacrolimus
+
++
-
-
(+)
-
-
Sirolimus
(+)
-
-
-
-
-
-
Citation: Salvadori M, Tsalouchos A. Pharmacogenetics of immunosuppressant drugs: A new aspect for individualized therapy. World J Transplant 2020; 10(5): 90-103