Pharmacogenetics of immunosuppressant drugs: A new aspect for individualized therapy

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

Level of recommendation: 1: Highly recommended candidate; 2: Recommended candidate; 3: Potential candidate; 4: Candidate to exclude. SNP: Single-nucleotide polymorphism; CNI: Calcineurin inhibitor; LOR: Level of recommendation; MAF: Minor allele frequency; NA: Not available; QOE : Quality of evidence.

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)

TAC: Tacrolimus; SNP: Single-nucleotide polymorphism.

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

TAC: Tacrolimus.

Table 4 Amount of variability in tacrolimus troughs that can be explained in African American model[39]

Model	Variation of tacrolimus troughs	Variation explained by model
Simple time-trend model	0.3114	-
Clinical variables	0.2497	19.8%
Clinical variables + rs776746	0.1929	39.1%
Clinical variables + rs10264272	0.2495	19.9%
Clinical variables + rs41303343	0.2310	25.8%
Clinical variables + rs776746 + rs10264272	0.1845	40.7%
Clinical variables + rs776746 + rs41303343	0.1553	50.1%
Clinical variables + rs776746 + rs10264272 + rs41303343	0.1436	53.9%

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

Level of recommendation: 1: Highly recommended candidate; 2: Recommended candidate; 3: Potential candidate; 4: Candidate to exclude. SNP: Single-nucleotide polymorphism; mTORI: Mammalian target of rapamycin inhibitors; LOR: Level of recommendation; MAF: Minor allele frequency; QOE: Quality of evidence.

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

Level of recommendation: 1: Highly recommended candidate; 2: Recommended candidate; 3: Potential candidate; 4: Candidate to exclude. SNP: Single-nucleotide polymorphism; MPA: Mycophenolic acid; IMPDH: Inosine monophosphate dehydrogenase; LOR: Level of recommendation; MAF: Minor allele frequency; QOE: Quality of evidence.

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

OR: Odds ratio; CI: Confidence interval; AR: Acute rejection; SNPs: Single-nucleotide polymorphisms; EC-MPS: Enteric coated mycophenolate sodium.

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	(+)	-	-	-	-	-	-

IMPDH: Inosine monophosphate dehydrogenase.