Effect of a New Functional
            <i>CYP3A4</i>
            Polymorphism on Calcineurin Inhibitors‘ Dose Requirements and Trough Blood Levels in Stable Renal Transplant Patients

Elens, Laure; Schaik, Ron H.N. van; Panin, Nadtha; Meyer, Martine De; Wallemacq, Pierre; Lison, Dominique; Mourad, Michel; Haufroid, Vincent

doi:10.2217/pgs.11.90

Cited by 139 publications

(120 citation statements)

References 42 publications

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“…Based on these observations, it has been proposed to prescribe different Tac doses for ultrarapid (CYP3A5 expressers and CYP3A4*1/*1), intermediate (CYP3A5 non-expressers and CYP3A4*1/*1) and poor (CYP3A5 non-expressers and CYP3A4*22 carriers) CYP3A metabolizers, respectively. [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: 99%

“…Wang and Sadee [35] demonstrated that CYP3A4*22 increases the formation of the nonfunctional CYP3A4 splice variant with partial intron 6 retention, thereby reducing the production of functional fulllength CYP3A4 mRNA and reduced CYP3A4 enzymatic activity. Elens et al [36] were the first to find that the CYP3A4*22 variant is associated with lower Tac dose requirements after renal transplantation. When CYP3A4 and CYP3A5 genotypes of individual patients were combined, Elens et al were able to predict Tac dose requirements better compared with the CYP3A4 or CYP3A5 genotype alone.…”

Section: Cyp3a4mentioning

confidence: 99%

See 1 more Smart Citation

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

120

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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Section: Cyp3a4mentioning

confidence: 99%

Section: Cyp3a4mentioning

confidence: 99%

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

120

114

View full text Add to dashboard Cite

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“…As the CYP3A4*22 allele has been previously associated with a reduced tacrolimus clearance [1,2], it is not surprising that an algorithm that does not take into account the CYP3A4*22 genotype will overrate the individual's ability to metabolize the drug. Indeed, predose concentrations are thus underestimated and, as a result, a negative bias is observed.…”

Section: Boxmentioning

confidence: 99%

The CYP3A422* allele affects the predictive value of a pharmacogenetic algorithm predicting tacrolimus predose concentrations

Elens

Hesselink

Schaik

et al. 2013

Brit J Clinical Pharma

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“…Recently, a newly discovered polymorphism in CYP3A4 (cytochrome P450, family 3, subfamily A, polypeptide 4) intron 6 (rs35599367 CϾT; CYP3A4* 22), associated with decreased mRNA hepatic expression and enzymatic activity, was found to be significantly associated with increased cyclosporine and tacrolimus doseadjusted concentrations in kidney transplant recipients (12,13 ). The variant allele also resulted in a higher risk of decreasing glomerular function and worse creatinine clearance in cyclosporine-treated patients (14 ).…”

confidence: 99%

Effect of CYP3A422, POR28, and PPARA rs4253728 on Sirolimus In Vitro Metabolism and Trough Concentrations in Kidney Transplant Recipients

et al. 2013

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BACKGROUND Recent studies have identified new candidate polymorphisms in the genes related to CYP3A activity or calcineurin inhibitor dose requirements in kidney transplant recipients. These genes and polymorphisms are CYP3A4 (cytochrome P450, family 3, subfamily A, polypeptide 4) (rs35599367-C>T; *22); POR [P450 (cytochrome) oxidoreductase] (rs1057868-C>T; *28); and PPARA (peroxisome proliferator-activated receptor alpha) (rs4253728-G>A). We investigated the impact of these polymorphisms on sirolimus (SRL) in vitro hepatic metabolism, SRL trough concentrations (C0), and SRL adverse events in kidney transplant recipients. METHODS The clinical study included 113 stable kidney transplant patients switched from a calcineurin inhibitor to SRL (SRL C0 measured at 1, 3, and 6 months thereafter). We investigated SRL metabolism in vitro using human liver microsomes derived from individual donors (n = 31). Microsomes and patients were genotyped by use of Taqman® allelic discrimination assays. The effects of polymorphisms and covariates were studied using multilinear regression imbedded in linear mixed-effect models or logistic regressions. RESULTS In vitro, the CYP3A4*22 allele resulted in approximately 20% lower metabolic rates of SRL (P = 0.0411). No significant association was found between CYP3A4, CYP3A5, or PPARA genotypes and SRL dose, C0, or C0/dose in kidney transplant patients. POR*28 was associated with a minor but significant decrease in SRL log-transformed C0 [CT/TT vs CC, β = −0.15 (0.05); P = 0.0197] but this did not have any impact on the dose administered, which limited the relevance of the finding. After adjustment for nongenetic covariates and correction for false discovery finding, none of the single-nucleotide polymorphisms tested showed significant association with SRL adverse events. CONCLUSIONS These recently described polymorphisms do not seem to substantially influence the pharmacokinetics of SRL or the occurrence of SRL adverse events in kidney transplant recipients.

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Effect of a New Functional CYP3A4 Polymorphism on Calcineurin Inhibitors‘ Dose Requirements and Trough Blood Levels in Stable Renal Transplant Patients

Cited by 139 publications

References 42 publications

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

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

The CYP3A422* allele affects the predictive value of a pharmacogenetic algorithm predicting tacrolimus predose concentrations

Effect of CYP3A422, POR28, and PPARA rs4253728 on Sirolimus In Vitro Metabolism and Trough Concentrations in Kidney Transplant Recipients

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Effect of a New Functional CYP3A4 Polymorphism on Calcineurin Inhibitors‘ Dose Requirements and Trough Blood Levels in Stable Renal Transplant Patients

Cited by 139 publications

References 42 publications

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

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

The CYP3A4*22 allele affects the predictive value of a pharmacogenetic algorithm predicting tacrolimus predose concentrations

Effect of CYP3A4*22, POR*28, and PPARA rs4253728 on Sirolimus In Vitro Metabolism and Trough Concentrations in Kidney Transplant Recipients

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The CYP3A422* allele affects the predictive value of a pharmacogenetic algorithm predicting tacrolimus predose concentrations

Effect of CYP3A422, POR28, and PPARA rs4253728 on Sirolimus In Vitro Metabolism and Trough Concentrations in Kidney Transplant Recipients