Influence of Combined
            <i>CYP3A4</i>
            and
            <i>CYP3A5</i>
            Single-Nucleotide Polymorphisms on Tacrolimus Exposure in Kidney Transplant Recipients: A Study According to the Post-Transplant Phase

Aouam, Karim; Kolsi, Abdessalem; Kerkeni, Emna; Fredj, Nadia Ben; Chaabane, Amel; Monastiri, K.; Boughattas, Naceur A.

doi:10.2217/pgs.15.138

Cited by 31 publications

(26 citation statements)

References 26 publications

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“…Several studies have been conducted in North Africans in order to evaluate the effect of CYP3A5 variants on tacrolimus dosage and on tacrolimus blood concentrations normalized by the dose and proved that there is significant difference between renal transplant patients with the CYP3A5*1 allele compared to homozygotes for the CYP3A5*3 allele, especially during the early post-transplant phase ( Elmachad et al., 2012 ; Aouam et al., 2015 ). To our knowledge, this is the first study to examine the association of the CYP3A5*3 allele with tacrolimus dose requirements and C/D ratios in Egyptian kidney transplant recipients.…”

Section: Discussionmentioning

confidence: 99%

“…Studies published in other North African populations (Algerians, Morocco, Tunisians, Libyans) showed that the CYP3A5*3 allele was the most prevalent with a frequency that reaches even 90% (Novillo et al, 2015;Fernańdez-Santander et al, 2016), whereas in the African population as a whole is observed great diversity from 4 to 95% (Zhou et al, 2017). Several studies have been conducted in North Africans in order to evaluate the effect of CYP3A5 variants on tacrolimus dosage and on tacrolimus blood concentrations normalized by the dose and proved that there is significant difference between renal transplant patients with the CYP3A5*1 allele compared to homozygotes for the CYP3A5*3 allele, especially during the early post-transplant phase (Elmachad et al, 2012;Aouam et al, 2015). To our knowledge, this is the first study to examine the association of the CYP3A5*3 allele with tacrolimus dose requirements and C/D ratios in Egyptian kidney transplant recipients.…”

Section: Discussionmentioning

confidence: 99%

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CYP3A5 Gene-Guided Tacrolimus Treatment of Living-Donor Egyptian Kidney Transplanted Patients

et al. 2020

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Background Tacrolimus is an approved first-line immunosuppressive agent for kidney transplantations. Part of interindividual and interethnic differences in the response of patients to tacrolimus is attributed to polymorphisms at CYP3A5 metabolic enzyme. CYP3A5 gene expression status is associated with tacrolimus dose requirement in renal transplant recipients. Materials and Methods In this study, we determined the allelic frequency of CYP3A5*3 in 76 renal transplanted patients of Egyptian descent. Secondly, we evaluated the influence of the CYP3A5 gene variant on tacrolimus doses required for these patients as well on dose-adjusted tacrolimus trough-concentrations. Results The CYP3A5*3 variant was the most frequent allele detected at 85.53%. Additionally, our results showed that, mean tacrolimus daily requirements for heterozygous patients ( CYP3A5*1/*3 ) were significantly higher compared to homozygous patients ( CYP3A5*3/*3 ) during the first year after kidney transplantation. Conclusion This is the first study in Egypt contributing to the individualization of tacrolimus dosing in Egyptian patients, informed by the CYP3A5 genotype.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

CYP3A5 Gene-Guided Tacrolimus Treatment of Living-Donor Egyptian Kidney Transplanted Patients

et al. 2020

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“…This was consistent with the fact that CYP3A4 existed mostly in the gastrointestinal tract of the recipient and CYP3A5 presented mainly in the liver of the donor, both being sites of drug metabolism. Almost all studies had reported a lower Tac exposure and/or a higher dose requirement in individuals who were CYP3A5 expressors (harboring CYP3A5 *3 AA or AG genotype) than that in nonexpressors ( CYP3A5 *3 GG genotype ) [ 34 ]. Besides, Qiu XY et al observed in their study performed in 103 renal transplant recipients that the CYP3A4*1G AA genotype was found to have a lower dose-adjusted concentration [ 27 ].…”

Section: Discussionmentioning

confidence: 99%

A new donors’ CYP3A5 and recipients’ CYP3A4 cluster predicting tacrolimus disposition, and new-onset hypertension in Chinese liver transplant patients

Liu

Zhang

et al. 2017

Oncotarget

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AimThe purpose of the current study was to investigate individualized therapy of tacrolimus (Tac), as well as complications after liver transplantation (LT) with the known genetic determinants and clinical factors.MethodsIn this retrospective study, two cohorts (n=170) from the China Liver Transplant Registry (CLTR) database from July 2007 to March 2015 were included.ResultsBoth donors’ CYP3A5*3 and recipients’ CYP3A4*1G had a correlation with Tac pharmacokinetics at four weeks (all P<0.05), except recipients’ CYP3A4*1G nearly had an association at week 2 (P=0.055). The model of donors’ CYP3A5*3, recipients’ CYP3A4*1G, and total bilirubin (TBL), for the prediction of Tac disposition, was better than donors’ CYP3A5*3 only at week 1, 2, and 3 (P=0.010, P=0.007, and P=0.010, respectively), but not apparent at week 4 (P=0.297). Besides, when the P value was greater than or equal to 0.6685 after considering the false-positive rate R=10%, the patients were considered to have a faster metabolism, according to the mentioned model. Interestingly, we found that if more than or equal to two alleles A were present in the combination of donors’ CYP3A5*3 and recipients’ CYP3A4*1G genotype, there was a lower Tac C/D ration at week 1, 2, and 3 (P<0.001, P=0.001, and P<0.001), except at week 4 (P=0.082), and the probability of new-onset hypertension was lesser (P<0.001).ConclusionsThese data provided a potential basis for a comprehensive approach to predicting the Tac dose requirement in individual patients and provided a strategy for the effective prevention, early diagnosis of new-onset hypertension in Chinese LT recipients.

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“…In these patients, the CYP3A5 *3 polymorphism was associated with rapid worsening of hepatic damage, but CYP3A4 *1 carriers showed only a small effect. The findings therefore suggested that the CYP3A5 *3 variant that determines decreased CYP3A5 enzymatic activity[33] could influence hepatic and renal exposure to sorafenib, with severe associated damage.…”

Section: Pharmacogenetics Of Approved Drugsmentioning

confidence: 99%

Pharmacogenetics of the systemic treatment in advanced hepatocellular carcinoma

Mattia

Cecchin

Guardascione

et al. 2019

WJG

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Hepatocellular carcinoma (HCC) accounts for the majority of primary liver cancers. To date, most patients with HCC are diagnosed at an advanced tumor stage, excluding them from potentially curative therapies ( i.e ., resection, liver transplantation, percutaneous ablation). Treatments with palliative intent include chemoembolization and systemic therapy. Among systemic treatments, the small-molecule multikinase inhibitor sorafenib has been the only systemic treatment available for advanced HCC over 10 years. More recently, other small-molecule multikinase inhibitors ( e.g ., regorafenib, lenvatinib, cabozantinib) have been approved for HCC treatment. The promising immune checkpoint inhibitors ( e.g ., nivolumab, pembrolizumab) are still under investigation in Europe while in the US nivolumab has already been approved by FDA in sorafenib refractory or resistant patients. Other molecules, such as the selective CDK4/6inhibitors ( e.g ., palbociclib, ribociclib), are in earlier stages of clinical development, and the c-MET inhibitor tivantinib did not show positive results in a phase III study. However, even if the introduction of targeted agents has led to great advances in patient response and survival with an acceptable toxicity profile, a remarkable inter-individual heterogeneity in therapy outcome persists and constitutes a significant problem in disease management. Thus, the identification of biomarkers that predict which patients will benefit from a specific intervention could significantly affect decision-making and therapy planning. Germ-line variants have been suggested to play an important role in determining outcomes of HCC systemic therapy in terms of both toxicity and treatment efficacy. Particularly, a number of studies have focused on the role of genetic polymorphisms impacting the drug metabolic pathway and membrane translocation as well as the drug mechanism of action as predictive/prognostic markers of HCC treatment. The aim of this review is to summarize and critically discuss the pharmacogenetic literature evidences, with particular attention to sorafenib and regorafenib, which have been used longer than the others in HCC treatment.

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Influence of Combined CYP3A4 and CYP3A5 Single-Nucleotide Polymorphisms on Tacrolimus Exposure in Kidney Transplant Recipients: A Study According to the Post-Transplant Phase

Cited by 31 publications

References 26 publications

CYP3A5 Gene-Guided Tacrolimus Treatment of Living-Donor Egyptian Kidney Transplanted Patients

CYP3A5 Gene-Guided Tacrolimus Treatment of Living-Donor Egyptian Kidney Transplanted Patients

A new donors’ CYP3A5 and recipients’ CYP3A4 cluster predicting tacrolimus disposition, and new-onset hypertension in Chinese liver transplant patients

Pharmacogenetics of the systemic treatment in advanced hepatocellular carcinoma

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