Effect of Age and Allele Variants of CYP3A5, CYP3A4, and POR Genes on the Pharmacokinetics of Cyclosporin A in Pediatric Renal Transplant Recipients From Serbia

Cvetković, Mirjana; Živković, Maja; Bundalo, Maja; Gojković, Ivana; Spasojević-Dimitrijeva, Brankica; Stanković, Aleksandra; Kostić, Mirjana

doi:10.1097/ftd.0000000000000442

Cited by 14 publications

(10 citation statements)

References 41 publications

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“…Combining CYP3A4 and CYP3A5 genotypes, poor CYP3A-metabolizers presented cyclosporine C 0 /D 54% and 114% higher compared to intermediate and extensive CYP3A-metabolizers, respectively ( Elens et al, 2011c ). Two other studies could not confirm this correlation, possibly due to a smaller patient population [ n = 47, ( Cvetković et al, 2017 )], whereas Debette-Gratien et al studied 170 liver transplant recipients ( Debette-Gratien et al, 2016 ). For CYP3A4 ∗ 22 carriers, a 53% higher dose-adjusted cyclosporine peak concentration (C 2 /D) ( Lunde et al, 2014 ) and 15% lower cyclosporine clearance ( Moes et al, 2014 ) were found.…”

Section: Immunosuppressive Agentsmentioning

confidence: 99%

CYP3A4∗22 Genotyping in Clinical Practice: Ready for Implementation?

et al. 2021

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Cytochrome P450 3A4 (CYP3A4) is the most important drug metabolizing enzyme in the liver, responsible for the oxidative metabolism of ∼50% of clinically prescribed drugs. Therefore, genetic variation in CYP3A4 could potentially affect the pharmacokinetics, toxicity and clinical outcome of drug treatment. Thus far, pharmacogenetics for CYP3A4 has not received much attention. However, the recent discovery of the intron 6 single-nucleotide polymorphism (SNP) rs35599367C > T, encoding the CYP3A4∗22 allele, led to several studies into the pharmacogenetic effect of CYP3A4∗22 on different drugs. This allele has a relatively minor allele frequency of 3-5% and an effect on CYP3A4 enzymatic activity. Thus far, no review summarizing the data published on several drugs is available yet. This article therefore addresses the current knowledge on CYP3A4∗22. This information may help in deciding if, and for which drugs, CYP3A4∗22 genotype-based dosing could be helpful in improving drug therapy. CYP3A4∗22 was shown to significantly influence the pharmacokinetics of several drugs, with currently being most thoroughly investigated tacrolimus, cyclosporine, and statins. Additional studies, focusing on toxicity and clinical outcome, are warranted to demonstrate clinical utility of CYP3A4∗22 genotype-based dosing.

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Section: Immunosuppressive Agentsmentioning

confidence: 99%

CYP3A4∗22 Genotyping in Clinical Practice: Ready for Implementation?

et al. 2021

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“…Although Pop-PK studies of CsA have been extensively performed in recent years, only two have been undertaken in juvenile allo-HSCT patients [ 6 , 7 ]. According to reports, genetic polymorphisms have important implications for CsA pharmacokinetics [ 8 – 10 ]. CsA is mainly metabolized by the cytochrome P450 (CYP) isoenzymes CYP3A4 and CYP3A5 (mainly in the liver, and to a lesser extent in the kidney and intestine) [ 11 , 12 ] and is also a substrate of the P-glycoprotein (encoded by the ABCB1 gene), which is involved in the absorption and elimination of CsA [ 13 , 14 ].…”

Section: Introductionmentioning

confidence: 99%

“…Polymorphisms in the genes of those proteins could influence the pharmacokinetics of CsA [ 8 , 15 – 17 ]. Because cytochrome P450 oxidoreductase (POR) is the only obligate electron donor for all hepatic microsomal CYP enzymes [ 18 ], POR genetic polymorphisms could also affect CsA pharmacokinetics [ 10 , 19 ]. In addition, the pregnane X receptor (PXR) has been identified as the key nuclear receptor regulating the expression of CYP3A4, CYP3A5, and ABCB1 [ 20 , 21 ].…”

Section: Introductionmentioning

confidence: 99%

Population pharmacokinetics of cyclosporine in Chinese children receiving hematopoietic stem cell transplantation

et al. 2019

Acta Pharmacol Sin

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Cyclosporine (CsA) is characterized by a narrow therapeutic window and high interindividual pharmacokinetic variability, particularly in juvenile patients. The aims of this study were to build a population pharmacokinetic model of CsA in Chinese children with hematopathy who received allogeneic hematopoietic stem cell transplantation (allo-HSCT) and to identify covariates affecting CsA pharmacokinetics. A total of 86 Chinese children aged 8.4 ± 3.8 years (range 1.1–16.8 years) who received allo-HSCT were enrolled. Whole blood samples were collected before allo-HSCT. Genotyping was performed using an Agena MassARRAY system. A total of 1010 trough plasma concentration values of CsA and clinical data were collected. The population pharmacokinetic model of CsA was constructed using nonlinear mixed-effects modeling (NONMEM) software. The stability and performance of the final model were validated using bootstrapping and normalized prediction distribution errors. We showed that a one-compartment model with first-order elimination adequately described the pharmacokinetics of CsA. The typical values for clearance (CL) and volume of distribution (V) were 42.3 L/h and 3100 L, respectively. Body weight, postoperative days, CYP3A4*1 G genotype, estimated glomerular filtration rate and coadministration of triazole antifungal drugs were identified as significant covariates for CL. Weight and postoperative days were significant covariates for the V of CsA. Our model can be adopted to optimize the CsA dosing regimen for Chinese children with hematopathy receiving allo-HSCT.

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“…The lower bioavailability and higher clearance of cyclosporine in children than in adults were reported [ 38 ]. In younger ages, there is an association between POR*28 allele and CYP3A5*3 allele with higher cyclosporine dose requirements and lower concentration/dose ratio [ 39 ]. Considering the effect of differences in polymorphism, race, gender and age, the extrapolation of the result from this study that conducted in adult Asian males with untested polymorphism to other populations should be done with caution, since it is possible that the difference in pharmacokinetics of the drug in each population might yield a different outcome of pharmacokinetic interaction between cyclosporine and pomegranate juice.…”

Section: Discussionmentioning

confidence: 99%

Pomegranate Juice does not Affect the Bioavailability of Cyclosporine in Healthy Thai Volunteers

Anlamlert

Sermsappasuk

2020

CCP

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Background: It is still controversial whether pomegranate causes drug interactions. Pomegranate juice has been shown to inhibit CYP3A in-vitro and animal studies. The co-administration pomegranate juice with cyclosporine, a narrow therapeutic drug that is the substrate of CYP3A, which might lead to drug toxicity. The objective of this study is to investigate the effect of pomegranate juice on the pharmacokinetics of cyclosporine in healthy Thai volunteers. Methods: The study design was an open-label, randomized, single dose, crossover study with a 2-week washout period. Each fasting subject received 2 microemulsion tablets of 100 mg of cyclosporine with 500 ml of pomegranate juice (test) or 500 ml of water (control). Serial blood samples were collected up to 24 h after dosing, and blood samples were analyzed for cyclosporine concentrations by using chemiluminescent microparticle immunoassay. Fourteen healthy volunteers completed the study. Results: The 90% confidence intervals for the test/control ratio using logarithmically transformed data of area under the concentration-time curve (AUC) from time zero until the last measured concentration (AUC0-t), AUC from time zero to infinity (AUC0-∞), and maximum concentration (Cmax) were 91.6-105.6, 92.0-105.2 and 82.3-102.5, respectively. The results were within the accepted bioequivalence range for narrow therapeutic index drugs (90-111% for AUC and 80-125% for Cmax). There were no differences in adverse event between groups. Conclusion: Single dose administration of pomegranate juice with cyclosporine did not significantly affect the oral bioavailability of cyclosporine. However, further work is needed to thoroughly evaluate the effect of pomegranate on narrow therapeutic drugs.

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Effect of Age and Allele Variants of CYP3A5, CYP3A4, and POR Genes on the Pharmacokinetics of Cyclosporin A in Pediatric Renal Transplant Recipients From Serbia

Abstract: Younger age, POR28 allele, and CYP3A53 allele were associated with higher CsA dosing requirements and lower concentration/dose ratio. Pretransplant screening of relevant polymorphisms in accordance with age should be considered to adjust therapy.

Cited by 14 publications

References 41 publications

CYP3A4∗22 Genotyping in Clinical Practice: Ready for Implementation?

CYP3A4∗22 Genotyping in Clinical Practice: Ready for Implementation?

Population pharmacokinetics of cyclosporine in Chinese children receiving hematopoietic stem cell transplantation

Pomegranate Juice does not Affect the Bioavailability of Cyclosporine in Healthy Thai Volunteers

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Effect of Age and Allele Variants of CYP3A5, CYP3A4, and POR Genes on the Pharmacokinetics of Cyclosporin A in Pediatric Renal Transplant Recipients From Serbia

Abstract: Younger age, POR*28 allele, and CYP3A5*3 allele were associated with higher CsA dosing requirements and lower concentration/dose ratio. Pretransplant screening of relevant polymorphisms in accordance with age should be considered to adjust therapy.

Cited by 14 publications

References 41 publications

CYP3A4∗22 Genotyping in Clinical Practice: Ready for Implementation?

CYP3A4∗22 Genotyping in Clinical Practice: Ready for Implementation?

Population pharmacokinetics of cyclosporine in Chinese children receiving hematopoietic stem cell transplantation

Pomegranate Juice does not Affect the Bioavailability of Cyclosporine in Healthy Thai Volunteers

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Abstract: Younger age, POR28 allele, and CYP3A53 allele were associated with higher CsA dosing requirements and lower concentration/dose ratio. Pretransplant screening of relevant polymorphisms in accordance with age should be considered to adjust therapy.