CYP3A5 polymorphisms and their effects on tacrolimus exposure in an ethnically diverse South African renal transplant population

Muller, Wim; Dandara, Collet; Manning, Kathryn; Mhandire, Doreen; Ensor, Jason; Barday, Zunaid; Freercks, Robert

doi:10.7196/samj.2020.v110i2.13969

Cited by 16 publications

(13 citation statements)

References 35 publications

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“…In this regard, Cheung et al studied a population of 86 adult Chinese kidney transplant patients and found that CYP3A5 expressers needed a higher TAC dose compared with the nonexpressers [ 25 ]. Similar results were shown in several other studies conducted in different ethnic groups and post-transplant time periods [ 26 , 27 , 28 , 29 , 30 ] and by Muller et al, who also found that CYP3A5*3/*3 carriers showed higher inter-patient variability than CYP3A5*1/*1 and *1/*3 carriers [ 31 ]. Similarly, Gervasini et colleagues observed that CYP3A5 expressers required a higher TAC dose than nonexpressers, also showing a lower pre-dose concentration [ 32 ].…”

Section: Resultssupporting

confidence: 89%

Use of Pharmacogenetics to Optimize Immunosuppressant Therapy in Kidney-Transplanted Patients

et al. 2022

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Immunosuppressant drugs (ISDs) are routinely used in clinical practice to maintain organ transplant survival. However, these drugs are characterized by a restricted therapeutic index, a high inter- and intra-individual pharmacokinetic variability, and a series of severe adverse effects. In particular, genetic factors have been estimated to play a role in this variability because of polymorphisms regarding genes encoding for enzymes and transporters involved in the ISDs pharmacokinetic. Several studies showed important correlations between genetic polymorphisms and ISDs blood levels in transplanted patients; therefore, this review aims to summarize the pharmacogenetics of approved ISDs. We used PubMed database to search papers on pharmacogenetics of ISDs in adults or pediatric patients of any gender and ethnicity receiving immunosuppressive therapy after kidney transplantation. We utilized as search term: “cyclosporine or tacrolimus or mycophenolic acid or sirolimus or everolimus and polymorphism and transplant”. Our data showed that polymorphisms in CYP3A5, CYP3A4, ABCB1, and UGT1A9 genes could modify the pharmacokinetics of immunosuppressants, suggesting that patient genotyping could be a helpful strategy to select the ideal ISDs dose for each patient.

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Section: Resultssupporting

confidence: 89%

Use of Pharmacogenetics to Optimize Immunosuppressant Therapy in Kidney-Transplanted Patients

et al. 2022

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“…In agreement with our findings, it has been observed that CYP3A5 expression is not associated with IPV of clearance, absolute concentration, or predicted area under the concentration-time curve (AUC) of tacrolimus among stable adult KTRs in previous studies [ 10 , 25 , 26 , 27 , 28 ]. In two studies by Pashaee et al [ 25 ] and Spierings et al [ 26 ], the proportions of KTRs with IPV of relative clearances of tacrolimus lower than the median values observed were comparable between CYP3A5 expressers and nonexpressers.…”

Section: Discussionsupporting

confidence: 93%

“…Given the fact that CYP3A5 expressers require a dose of tacrolimus approximately twice as high as CYP3A5 nonexpressers to achieve the same tacrolimus levels, it has been hypothesized that CYP3A5 expressers could be more susceptible to higher IPV [ 32 ]. On the other hand, it has also been postulated that since tacrolimus metabolism in CYP3A5 nonexpressers relies predominantly on the activity of CYP3A4 which is much more prone to induction and inhibition [ 33 ], CYP3A5 nonexpressers might be more susceptible to higher IPV [ 28 ]. The results of the present study do not support these hypotheses.…”

Section: Discussionmentioning

confidence: 99%

“…Whereas, only around 15% of Caucasians are CYP3A5 expressers, 45 to 70% of African Americans and approximately 50% of Asians are CYP3A5 expressers [ 22 , 23 , 24 ]. Limited information regarding the association between the CYP3A5 genetic polymorphisms and IPV of tacrolimus pharmacokinetics is available [ 10 , 25 , 26 , 27 , 28 ]. The extent to which the CYP3A5 polymorphisms affect tacrolimus IPV of dose-adjusted tacrolimus trough concentrations (C0/D) has not been explored in a population in which a prevalence of CYP3A5 expressers is high.…”

Section: Introductionmentioning

confidence: 99%

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Comparison of Tacrolimus Intra-Patient Variability during 6–12 Months after Kidney Transplantation between CYP3A5 Expressers and Nonexpressers

Nuchjumroon

Vadcharavivad

Singhan

et al. 2022

JCM

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A high intra-patient variability (IPV) of tacrolimus exposure is associated with poor long-term kidney transplantation outcomes. To assess the influence of cytochrome P450 (CYP) 3A5 genetic polymorphisms on tacrolimus IPV, 188 clinically stable kidney transplant recipients, who had received an immediate-release tacrolimus-based immunosuppressive regimen, were enrolled in this retrospective cohort study. Genotyping of CYP3A5*3 (rs776746) was performed and 110 (58.5%) were identified as CYP3A5 expressers and 78 (41.5%) as nonexpressers. Whole blood tacrolimus concentrations were analyzed by chemiluminescent microparticle immunoassay. Dose-adjusted trough tacrolimus concentrations (C0/D) measured at months 6, 9, and 12 were used to determine IPV. There were no significant differences in the IPV estimated by the coefficient of variation, the IPV calculated by mean absolute deviation method, and the proportions of recipients with the IPV estimated by the coefficient of variation of 30% or more between CYP3A5 expressers and nonexpressers (p = 0.613, 0.686, and 0.954, respectively). Tacrolimus C0/D in CYP3A5 expressers was approximately half of those in nonexpressers, overall (p < 0.001). In both CYP3A5 expressers and nonexpressers, tacrolimus C0/D increased gradually from month 6 to month 12 (p = 0.021). There was no evidence that the CYP3A5 polymorphisms significantly influence tacrolimus IPV during the 6 to 12 months after kidney transplantation.

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“…10 In view of the high prevalence of CYP3A5 expression in South African transplant recipients, high tacrolimus dose requirements are often necessary and result in substantially increased immunosuppression costs. 16 Nevertheless, in view of patient safety concerns, the continued mandatory use of PIs was reconsidered in 2014. 12 TDF has been well described to be associated with tubular nephrotoxicity.…”

Section: Discussionmentioning

confidence: 99%

Retrospective Review of ART Regimens in HIV-Positive to HIV-Positive Kidney Transplant Recipients

Barday

Manning²,

Freercks³

et al. 2022

Kidney International Reports

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CYP3A5 polymorphisms and their effects on tacrolimus exposure in an ethnically diverse South African renal transplant population

Abstract: This open-access article is distributed under Creative Commons licence CC-BY-NC 4.0.

Cited by 16 publications

References 35 publications

Use of Pharmacogenetics to Optimize Immunosuppressant Therapy in Kidney-Transplanted Patients

Use of Pharmacogenetics to Optimize Immunosuppressant Therapy in Kidney-Transplanted Patients

Comparison of Tacrolimus Intra-Patient Variability during 6–12 Months after Kidney Transplantation between CYP3A5 Expressers and Nonexpressers

Retrospective Review of ART Regimens in HIV-Positive to HIV-Positive Kidney Transplant Recipients

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