Genetic Polymorphisms and Individualized Tacrolimus Dosing

Soria, M.A. López-Montenegro; Berga, J. Kanter; Catalán, Sandra Beltrán; Milara, Javier; Mateu, L.M. Pallardó; Torres, Nicolás

doi:10.1016/j.transproceed.2010.08.001

Cited by 32 publications

(18 citation statements)

References 11 publications

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“…Others found no difference in tacrolimus concentrations between CYP3A5*1/*1 and *1/*6 genotypes groups although the number of subjects was small. ( 56 ) In another study, CYP3A5*1/*1, *1/*3 or *1/*6 carriers had lower tacrolimus troughs than CYP3A5*3/*3 carriers but no difference in area under the curve although only one individual carried the CYP3A5*1/*6 genotype. ( 54 ) The influence of CYP3A5*6 and CYP3A5*7 alleles has been studied towards other CYP3A5 substrates and the effect may be substrate specific therefore our results may not be generalizable to other drugs.…”

Section: Discussionmentioning

confidence: 98%

Genotype-guided tacrolimus dosing in African-American kidney transplant recipients

et al. 2015

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Tacrolimus is dependent on CYP3A5 enzyme for metabolism. Expression of the CYP3A5 enzyme is controlled by several alleles including CYP3A5*1, CYP3A5*3, CYP3A5*6 and CYP3A5*7. African Americans (AA) have on average higher tacrolimus dose requirements than Caucasians; however, some have requirements similar to Caucasians. Studies in AA have primarily evaluated the CYP3A5*3 variant; however, there are common nonfunctional variants in AA (CYP3A5*6 and CYP3A5*7) which do not occur in Caucasians. These variants are associated with lower dose requirements and may explain why some AA are metabolically similar to Caucasians. We created a tacrolimus clearance model in 354 AA using a development and validation cohort. Time posttransplant, steroid and antiviral use, age, CYP3A5*1, *3, *6 and *7 alleles were significant towards clearance. This study is the first to develop an AA specific genotype-guided tacrolimus dosing model to personalize therapy.

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Section: Discussionmentioning

confidence: 98%

Genotype-guided tacrolimus dosing in African-American kidney transplant recipients

et al. 2015

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“…MDR1 has multiple polymorphisms; 1236C>T, 2677G>T/A, and 3435C>T were identified as better predictors of the blood concentration of CNIs than 1236C>T and 2677G>T/A [77,78]. It has been reported that the 3435C>T polymorphism is associated with higher CNI concentrations [79][80][81][82], but many studies suggest that MDR1 polymorphisms (even 3435C>T) do not influence the CNI concentrations in Asian patients [47,[83][84][85][86][87]. Consequently, ethnicity may be a stronger factor affecting the association between the MDR1 polymorphisms and CNI concentrations in blood.…”

Section: Biomarkersmentioning

confidence: 99%

Biomarkers for individualized dosage adjustments in immunosuppressive therapy using calcineurin inhibitors after organ transplantation

Tajima

Suetsugu

et al. 2018

Acta Pharmacol Sin

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Calcineurin inhibitors (CNIs), such as cyclosporine A and tacrolimus, are widely used immunosuppressive agents for the prevention of post-transplantation rejection and have improved 1-year graft survival rates by up to 90%. However, CNIs can induce severe reactions, such as acute or chronic allograft nephropathy, hypertension, and neurotoxicity. Because CNIs have varied bioavailabilities, narrow therapeutic ranges, and individual propensities for toxic effects, therapeutic drug monitoring is necessary for all CNIs. Identifying the genetic polymorphisms in drug-metabolizing enzymes will help to determine personalized dosage regimens for CNIs, as CNIs are substrates for CYP3A5 and P-glycoprotein (P-gp, MDR1). CNIs are often concomitantly administered with voriconazole or proton pump inhibitors (PPIs), giving rise to drug interaction problems. Voriconazole and PPIs can increase the blood concentrations of CNIs, and both are primarily metabolized by CYP2C19. Thus, it is expected that interactions between CNIs and voriconazole or PPI would be affected by CYP2C19 and CYP3A5 polymorphisms. CNI-induced acute kidney injury (AKI) is a serious complication of transplantations. Neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule 1 (KIM-1) are noninvasive urinary biomarkers that are believed to be highly sensitive to CNI-induced AKI. In this article, we review the adverse events and pharmacokinetics of CNIs and the biomarkers related to CNIs, including CYP3A5, CYP2C19, MDR1, NGAL, and KIM-1. We hope that these data will help to identify the optimal biomarkers for monitoring CNI-based immunosuppressive therapy after organ transplantation.

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“…The calcineurin inhibitors (CNI), tacrolimus (TAC) are the most widely used immunosuppression drugs to prevent allograft rejection after solid organ transplantation. Both these drugs display a narrow therapeutic index and high inter-individual pharmacokinetic variability, so monitoring their blood levels is required to avoid rejection and reduce toxicity (López-Montenegro Soria et al 2010 ). Sirolimus (SRL) is another immunosuppressant by replacing the CNIs to prevent progression in chronic kidney disease (CKD) following organ transplantation.…”

Section: Introductionmentioning

confidence: 99%

CYP3A5 and ABCB1 genotype influence tacrolimus and sirolimus pharmacokinetics in renal transplant recipients

Lin

Shi

et al. 2015

SpringerPlus

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CYP3A5 and ABCB1 polymorphisms have been shown to influence tacrolimus blood concentrations and dose requirements, but the conclusion in the current reports were inconformity. Sirolimus are also metabolized by CYP3A subfamily and are substrates of the P-gp. The aim was to determine whether these polymorphisms affect tacrolimus (TAC) and sirolimus (SRL) trough concentrations and dose requirements after renal transplantation. 153 renal transplant recipients were enrolled into this study, 112 were treated with TAC-based regimen, Another 43 recipients received SRL-based regimen. The recipients’ mean follow-up time was 20 mo (range 15–27 mo). All renal transplant recipients were all in a stable stage. The trough concentration and daily dose of TAC and SRL were gained from each recipient. All recipients were genotyped for CYP3A5 (6986A>G), CYP3A4 intron 6 (CYP3A4*22), CYP3A4*18, ABCB1 exon 26 (3435C>T), exon 12 (1236C>T) and 2677G>T/A SNPs by HRM analysis (high-resolution melting curve analysis). The TAC and SRL concentration/dose ratio (C/D) in recipients with CYP3A5 (*)3/(*)3 were significantly higher than that of those with (*)1 allele (P < 0.05). However, there was no significant correlation between adjusted TAC and SRL trough concentrations or dose requirements with CYP3A4 and ABCB1 SNPs genetic polymorphisms. In recipients with TAC-based or SRL-based therapy, the CYP3A5 genes (6986A>G) can influence the TAC and SRL pharmacokinetics in renal transplant recipients.

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Genetic Polymorphisms and Individualized Tacrolimus Dosing

Cited by 32 publications

References 11 publications

Genotype-guided tacrolimus dosing in African-American kidney transplant recipients

Genotype-guided tacrolimus dosing in African-American kidney transplant recipients

Biomarkers for individualized dosage adjustments in immunosuppressive therapy using calcineurin inhibitors after organ transplantation

CYP3A5 and ABCB1 genotype influence tacrolimus and sirolimus pharmacokinetics in renal transplant recipients

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