The Role of Pharmacogenetics in the Disposition of and Response to Tacrolimus in Solid Organ Transplantation

Abstract

The calcineurin inhibitor tacrolimus is the backbone of immunosuppressive drug therapy after solid organ transplantation. Tacrolimus is effective in preventing acute rejection but has considerable toxicity and displays marked inter-individual variability in its pharmacokinetics and pharmacodynamics. The genetic basis of these phenomena is reviewed here. With regard to its pharmacokinetic variability, a single nucleotide polymorphism (SNP) in cytochrome P450 (CYP) 3A5 (6986A>G) has been consistently associated with tacrolimus dose requirement. Patients expressing CYP3A5 (those carrying the A nucleotide, defined as the *1 allele) have a dose requirement that is around 50 % higher than non-expressers (those homozygous for the G nucleotide, defined as the *3 allele). A randomised controlled study in kidney transplant recipients has demonstrated that a CYP3A5 genotype-based approach to tacrolimus dosing leads to more patients reaching the target concentration early after transplantation. However, no improvement of clinical outcomes (rejection incidence, toxicity) was observed, which may have been the result of the design of this particular study. In addition to CYP3A5 genotype, other genetic variants may also contribute to the variability in tacrolimus pharmacokinetics. Among these, the CYP3A4*22 and POR*28 SNPs are the most promising. Individuals carrying the CYP3A4*22 T-variant allele have a lower tacrolimus dose requirement than individuals with the CYP3A4*22 CC genotype and this effect appears to be independent of CYP3A5 genotype status. Individuals carrying the POR*28 T-variant allele have a higher tacrolimus dose requirement than POR*28 CC homozygotes but this association was only found in CYP3A5-expressing individuals. Other, less well-defined SNPs have been inconsistently associated with tacrolimus dose requirement. It is envisaged that in the future, algorithms incorporating clinical, demographic and genetic variables will be developed that will aid clinicians with the determination of the tacrolimus starting dose for an individual transplant recipient. Such an approach may limit early tacrolimus under-exposure and toxicity. With regard to tacrolimus pharmacodynamics, no strong genotype-phenotype relationships have been identified. Certain SNPs associate with rejection risk but these observations await replication. Likewise, the genetic basis of tacrolimus-induced toxicity remains unclarified. SNPs in the genes encoding for the drug transporter ABCB1 and the CYP3A enzymes may relate to chronic nephrotoxicity but findings have been inconsistent. No genetic markers reliably predict new-onset diabetes mellitus after transplantation, hypertension or neurotoxicity. The CYP3A5*1 SNP is currently the most promising biomarker for tailoring tacrolimus treatment. However, before CYP3A5 genotyping is incorporated into the routine clinical care of transplant recipients, prospective clinical trials are needed to determine whether such a strategy improves patient outcomes. The role of pharmacogenetics in tacrolimus pharmac...

Pharmacogenetic aspects of the use of tacrolimus in renal transplantation: recent developments and ethnic considerations

“…[12] Individuals homozygous for the CYP3A5*3 allele are referred to as CYP3A5 non-expressers, whereas individuals carrying at least one CYP3A5*1 allele are known as CYP3A5 expressers. The reduced enzymatic activity associated with the CYP3A5*3 allele has been associated with a reduced Tac dose requirement (for a review, see reference [13]). CYP3A5 expressers require a Tac dose that is about 50% higher than that of CYP3A5 non-expressers to reach the same exposure.…”

IL-3 and CTLA4 gene polymorphisms may influence the tacrolimus dose requirement in Chinese kidney transplant recipients

“…Some clinical factors and genetic factors play critical roles in determining TAC pharmacokinetics (PK) [9][10][11] . Tacrolimus is known to be transported by P-glycoprotein (MDR1 or ABCB1) and metabolized by cytochrome P450 (CYP) 3A4 and CYP3A5.…”

Investigation of CYP 3A5 and ABCB1 gene polymorphisms in the long-term following renal transplantation: Effects on tacrolimus exposure and kidney function

“…The controversy in the results concerning the long-term adverse effects of Tac prompted an assessment of the contribution of CYP 3A5 and ABCB1 polymorphisms on renal function parameters in transplant recipients in the present study. The majority of the previous studies found no correlation between investigated polymorphisms and the clinical features of Tac toxicity or renal function attenuation (6,8,31). The bivariate linear regression showed that CYP 3A5 polymorphism, but not ABCB1 polymorphism, independently affects renal function from 6 to 24 months after renal transplantation (Table V).…”

“…The ABCB1 gene is also polymorphically expressed with ≥50 different polymorphisms known to date. In contrast to CYP 3A5, neither of the ABCB1 polymorphisms leads to complete loss of the PGP function (5,8). The most studied ABCB1 gene polymorphism is 3435C>T, which includes a C to T transition at position 3435 within exon 26.…”

“…By contrast, non-expressers do not have a functionally active enzyme and carry the CYP 3A5 * 3/ * 3 genotype (3,5). The significance of this gene polymorphism on Tac pharmacokinetics is well documented, while its role in the pharmacodynamics of Tac has not been elucidated completely (6)(7)(8). Tac is also a substrate of P-glycoprotein (PGP), the product of the ATP-binding cassette transporter (ABCB1) gene, which acts as an efflux transporter that limits ALEKSANDRA M. IGNJATOVIĆ 4 , GORAN J. PAUNOVIĆ 3 and RADMILA M. VELIČKOVIĆ-RADOVANOVIĆ the oral absorption of drugs.…”