Individualized immunosuppression in transplant patients: potential role of pharmacogenetics

Figures & data

Table 1 Induction immunosuppression drugs

Drug	Mechanism of action	Side effects
ATG/ALG	Complement mediated lysis Opsonization and clearance blockade of cell surface receptors	Agranulocytosis Thrombocytopenia Cytokine release syndrome
Basiliximab (anti-CD25 antibody)	Blockade of IL-2 receptor
Alemtuzumab	T and B lymphocyte depletion	Cytokine release syndrome
OKT3	Complement-mediated lysis opsonization and clearance blockade of CD3 receptor	Cytokine release syndrome

Abbreviations: ATG, antithymocyte globulin; ALG, antilymphocyte globulin; IL-2, interleukin-2; OKT3, monoclonal anti-CD3 antibody.

Table 2 Maintenance immunosuppression drugs

Drug	Mechanism of action	Side effects
Corticosteroids	Blocks transcription of cytokine genes, IL-1, IL-2, IL-3, IL-5, IL-6, tumor necrosis factor-α, and interferons	Hypertension
		Glucose intolerance
		Dyslipidemia
		Osteoporosis
Cyclosporin	Inhibits IL-2 production, stimulates TGF-β production	Nephrotoxicity
		Hypertension
		Dyslipidemia
		Glucose intolerance
Tacrolimus	Inhibits IL-2 production	Nephrotoxicity
		Hypertension
		Dyslipidemia
		Glucose intolerance
Azathioprine	Inhibits purine synthesis and blocks DNA and RNA synthesis Inhibits CD28 signaling	Myelosuppression
Mycohphenolate mofetil	Blocks de novo pathway of purine synthesis (selective for lymphocytes) and blocks glycosylation	Diarrhea and gastrointestinal upset Myelosuppression
Sirolimus/everolimus	Blocks IL-2-induced cell cycle progression	Hyperlipidemia
		Thrombocytopenia
		Impaired wound healing
		Oral ulcers
Belatacept	Blocks costimulation by CD28	PTLD in EBV naïve patients

Abbreviations: EBV, Epstein–Barr virus; IL, interleukin; PTLD, posttransplant lymphoproliferative disorder; TGF, transforming growth factor.

Table 3 Summary of potential pharmacogenetic strategies to guide immunosuppressive drug prescribing

Drug	Genotypes	Evidence	Ref
Tacrolimus	CYP3A5*1/*3	Tested in a randomized controlled trial with earlier achievement of target blood concentrations but no influence on clinical outcome.	^Citation58
			^Citation59
	CYP3A4*22	May provide additional predictive value to algorithms in combination with CYP3A5*1/*3.	^Citation60
	POR*28		^Citation61
Sirolimus	CYP3A5*1/*3	Impact on dose-normalized blood concentrations but not yet tested in a clinical trial.	^Citation67^–^Citation69
Cyclosporin	CYP3A5*1/*3	Combination of genotypes may predict drug exposure but not yet replicated.	^Citation66
	CYP3A4*22
Azathioprine	TPMT	Predicts individuals likely to develop severe myelotoxicity. Limited adoption in transplantation with no intervention study data.	^Citation51
Mycophenolate	UGT1A9	Predicts individuals likely to be under-exposed to MPA with increased risk of rejection.	^Citation71
	IMPDH1	Predicts individuals at increased risk of rejection. Genetic component to variability in MPA exposure is much smaller than other factors, limiting the potential of pharmacogenetics.	^Citation72

Abbreviations: IMPDH, inosine monophosphate dehydrogenase; MPA, mycophenolic acid.

HesselinkDAvan SchaikRHvan AgterenMCYP3A5 genotype is not associated with a higher risk of acute rejection in tacrolimus-treated renal transplant recipientsPharmacogenet Genomics20081833934818334918

 PubMed Web of Science ®Google Scholar

ThervetELoriotMABarbierSOptimization of initial tacrolimus dose using pharmacogenetic testingClin Pharmacol Ther20108772172620393454

 PubMed Web of Science ®Google Scholar

ElensLBouamarRHesselinkDAA new functional CYP3A4 intron 6 polymorphism significantly affects tacrolimus pharmacokinetics in kidney transplant recipientsClin Chem2011571574158321903774

 PubMed Web of Science ®Google Scholar

de JongeHMetalidisCNaesensMLambrechtsDKuypersDRThe P450 oxidoreductase *28 SNP is associated with low initial tacrolimus exposure and increased dose requirements in CYP3A5-expressing renal recipientsPharmacogenomics2011121281129121770725

 PubMed Web of Science ®Google Scholar

AnglicheauDLe CorreDLechatonSConsequences of genetic polymorphisms for sirolimus requirements after renal transplant in patients on primary sirolimus therapyAm J Transplant2005559560315707415

 PubMed Web of Science ®Google Scholar

MiaoLYHuangCRHouJQQianMYAssociation study of ABCB1 and CYP3A5 gene polymorphisms with sirolimus trough concentration and dose requirements in Chinese renal transplant recipientsBiopharm Drug Dispos2007291517941052

 PubMed Web of Science ®Google Scholar

ElensLvan SchaikRHPaninNEffect of a new functional CYP3A4 polymorphism on calcineurin inhibitors dose requirements and trough blood levels in stable renal transplant patientsPharmacogenomics2011121383139621902502

 PubMed Web of Science ®Google Scholar

EvansWEThiopurine S-methyltransferase: a genetic polymorphism that affects a small number of drugs in a big wayPharmacogenetics20021242142312172209

 PubMedGoogle Scholar

van SchaikRHvanAMde FijterJWUGT1A9-275T>A/-2152C>T polymorphisms correlate with low MPA exposure and acute rejection in MMF/tacrolimus-treated kidney transplant patientsClin Pharmacol Ther20098631932719494809

 PubMed Web of Science ®Google Scholar

WangJYangJWZeeviAIMPDH1 gene polymorphisms and association with acute rejection in renal transplant patientsClin Pharmacol Ther20078371171717851563

 PubMed Web of Science ®Google Scholar