<i>CYP3A4*22</i>
            and
            <i>CYP3A</i>
            Combined Genotypes Both Correlate With Tacrolimus Disposition in Pediatric Heart Transplant Recipients

Gijsen, Violette M G J; Schaik, Ron H.N. van; Elens, Laure; Soldin, Steven J.; Koren, Gideon; Wildt, Saskia N. de

doi:10.2217/pgs.13.80

Cited by 49 publications

(51 citation statements)

References 24 publications

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“…Another study found that the rs4646437 C>T polymorphism could potentially affect the interindividual variability in tacrolimus metabolism among Chinese renal transplant recipients [33]. Tacrolimus is metabolized mainly by CYP3A4 and CYP3A5 [34]. This finding is consistent with the present results.…”

Section: Discussionsupporting

confidence: 92%

Effects of CYP3A4 polymorphisms on the plasma concentration of voriconazole

Sun

Ren

et al. 2014

Eur J Clin Microbiol Infect Dis

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Voriconazole is frequently utilized for the prevention and treatment of invasive fungal infections (IFIs), and is extensively metabolized by the cytochrome P450 (CYP) system. The impact of activity of the genes encoding CYP3A4, CYP3A5, and CYP2C9 on the pharmacokinetics of voriconazole cannot be ignored because, second to CYP2C19, they are the most important enzymes involved in voriconazole metabolism. The influence of genetic polymorphisms in CYP3A4, CYP3A5, and CYP2C9 on the plasma concentrations of voriconazole was evaluated in the present study. The study cohort comprised 158 patients with IFIs in whom 22 single-nucleotide polymorphisms (SNPs) in CYP3A4, CYP3A5, and CYP2C9 were genotyped using the Sequenom MassARRAY RS1000 system, and voriconazole plasma concentrations were measured by high-performance liquid chromatography (HPLC). 40, 91, and 27 patients presented with low (<1 mg/L), normal (1-4 mg/L), and high (>4 mg/L) plasma voriconazole concentrations, respectively. Correlation analysis between polymorphisms and the plasma voriconazole concentration revealed an association between the presence of the rs4646437 T allele and a higher plasma voriconazole concentration [p = 0.033, odds ratio (OR) = 2.832, 95% confidence interval (CI) = 1.086-7.384]. This study has identified a new SNP related to the metabolism of voriconazole, potentially providing novel insight into the influence of CYP3A4 on the pharmacokinetics of this antifungal agent.

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Section: Discussionsupporting

confidence: 92%

Effects of CYP3A4 polymorphisms on the plasma concentration of voriconazole

Sun

Ren

et al. 2014

Eur J Clin Microbiol Infect Dis

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“…[36][37][38] In pediatric heart transplantation, an association between CYP3A4*22 and Tac dose requirement has also been observed. [39] CYP3A4*22 carriers needed 30% less Tac to reach similar target concentrations compared with CYP3A4*1/*1 carriers.…”

Section: Cyp3a4mentioning

confidence: 91%

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

Tang

Andrews

Gelder

et al. 2016

Expert Opinion on Drug Metabolism & Toxicology

117

114

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Introduction: Tacrolimus (Tac) is effective in preventing acute rejection but has considerable toxicity and inter-individual variability in pharmacokinetics and pharmacodynamics. Part of this is explained by polymorphisms in genes encoding Tac-metabolizing enzymes and transporters. A better understanding of Tac pharmacokinetics and pharmacodynamics may help to minimize different outcomes amongst transplant recipients by personalizing immunosuppression. Areas covered: The pharmacogenetic contribution of Tac metabolism will be examined, with a focus on recent discoveries, new developments and ethnic considerations. Expert opinion: The strongest and most consistent association in pharmacogenetics is between the CYP3A5 genotype and Tac dose requirement, with CYP3A5 expressers having a~40-50% higher dose requirement compared to non-expressers. Two recent randomized-controlled clinical trials using CYP3A5 genotype, however, did not show a decrease in acute rejections nor reduced toxicity. CYP3A4*22, CYP3A4*26, and POR*28 are also associated with Tac dose requirements and may be included to provide the expected improvement of Tac therapy. Studies focusing on the intracellular drug concentrations and on calcineurin inhibitor-induced nephrotoxicity also seem promising. For all studies, however, the ethnic prevalence of genotypes should be taken into account, as this may significantly impact the effect of pre-emptive genotyping.ARTICLE HISTORY

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“…7,[9][10][11] Recently, a novel functional polymorphism in CYP3A4 (CYP3A4*22; rs35599367) was described and associated with lower CNI dose requirement in transplant patients. [12][13][14][15] Furthermore, polymorphisms in the P450 oxidoreductase (POR gene) and pregnane X receptor (PXR, NR1I2 gene) have been shown to modulate the activity of CYP3A enzymes and to alter the pharmacokinetics of TAC in kidney transplant patients. 16,17 Studying multiple polymorphisms in genes acting together on an immunosuppressive drug pathway instead of single variants may provide new insight into factors influencing the response.…”

Section: Introductionmentioning

confidence: 99%

CYP3A53 and POR28 Genetic Variants Influence the Required Dose of Tacrolimus in Heart Transplant Recipients

Lesche¹,

Sigurdardottir

Setoud

et al. 2014

Therapeutic Drug Monitoring

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Background: After heart transplantation (HTx), the interindividual pharmacokinetic variability of immunosuppressive drugs represents a major therapeutic challenge due to the narrow therapeutic window between over-immunosuppression causing toxicity and underimmunosuppression leading to graft rejection. Although genetic polymorphisms have been shown to influence pharmacokinetics of immunosuppressants, data in the context of HTx are scarce. We thus assessed the role of genetic variation in CYP3A4, CYP3A5, POR, NR1I2, and ABCB1 acting jointly in immunosuppressive drug pathways in tacrolimus (TAC) and ciclosporin (CSA) dose requirement in HTx recipients.Methods: Associations between 7 functional genetic variants and blood dose-adjusted trough (C 0 ) concentrations of TAC and CSA at 1, 3, 6, and 12 months after HTx were evaluated in cohorts of 52 and 45 patients, respectively.Results: Compared with CYP3A5 nonexpressors (*3/*3 genotype), CYP3A5 expressors (*1/*3 or *1/*1 genotype) required around 2.2-to 2.6-fold higher daily TAC doses to reach the targeted C 0 concentration at all studied time points (P # 0.003). Additionally, the POR*28 variant carriers showed higher dose-adjusted TAC-C 0 concentrations at all time points resulting in significant differences at 3 (P = 0.025) and 6 months (P = 0.047) after HTx. No significant associations were observed between the genetic variants and the CSA dose requirement.Conclusions: The CYP3A5*3 variant has a major influence on the required TAC dose in HTx recipients, whereas the POR*28 may additionally contribute to the observed variability. These results support the importance of genetic markers in TAC dose optimization after HTx.

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CYP3A422* and CYP3A Combined Genotypes Both Correlate With Tacrolimus Disposition in Pediatric Heart Transplant Recipients

Abstract: Analysis of CYP3A422, either alone or in combination with CYP3A53, may help towards individualization of tacrolimus therapy in pediatric heart transplant patients.

Cited by 49 publications

References 24 publications

Effects of CYP3A4 polymorphisms on the plasma concentration of voriconazole

Effects of CYP3A4 polymorphisms on the plasma concentration of voriconazole

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

CYP3A53 and POR28 Genetic Variants Influence the Required Dose of Tacrolimus in Heart Transplant Recipients

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CYP3A4*22 and CYP3A Combined Genotypes Both Correlate With Tacrolimus Disposition in Pediatric Heart Transplant Recipients

Abstract: Analysis of CYP3A4*22, either alone or in combination with CYP3A5*3, may help towards individualization of tacrolimus therapy in pediatric heart transplant patients.

Cited by 49 publications

References 24 publications

Effects of CYP3A4 polymorphisms on the plasma concentration of voriconazole

Effects of CYP3A4 polymorphisms on the plasma concentration of voriconazole

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

CYP3A5*3 and POR*28 Genetic Variants Influence the Required Dose of Tacrolimus in Heart Transplant Recipients

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CYP3A422* and CYP3A Combined Genotypes Both Correlate With Tacrolimus Disposition in Pediatric Heart Transplant Recipients

Abstract: Analysis of CYP3A422, either alone or in combination with CYP3A53, may help towards individualization of tacrolimus therapy in pediatric heart transplant patients.

CYP3A53 and POR28 Genetic Variants Influence the Required Dose of Tacrolimus in Heart Transplant Recipients