The genetic polymorphisms of POR*28 and CYP3A5*3 significantly influence the pharmacokinetics of tacrolimus in Chinese renal transplant recipients

Zhang, Jingjing; Liu, Shuaibing; Xue, Liang; Ding, Xiaoliang; Zhang, Hua; Miao, Liyan

doi:10.5414/cp202152

Cited by 45 publications

(28 citation statements)

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“…Contrasting with these observations, a number of previous studies have failed to highlight the benefit of introducing CYP3A4 ∗ 22 in modeling Tac inter-individual variability through popPK-approaches, with a few exceptions (Shi et al, 2011; Zuo et al, 2013; Zhang et al, 2015; Moes et al, 2016; Andreu et al, 2017). This is not surprising as the majority of studies were performed in Asian populations where CYP3A4 ∗ 22 is absent, as it is for individuals of African origins.…”

Section: Discussionmentioning

confidence: 94%

“…However, even if the amplitude of the CYP3A4 ∗ 22 effect might be comparable to that of CYP3A5 ∗ 3 , the CYP3A4 ∗ 22 influence is not as statistically significant probably because of the wide PK variability observed among the CYP3A4 ∗ 22 carriers. As a consequence, it may also explain why it is not always identified as a significant covariate when considering the few studies reported to date (Shi et al, 2011; Zuo et al, 2013; Zhang et al, 2015; Moes et al, 2016). Another possible explanation is the fact that CYP3A5 ∗ 3 completely blunts the CYP3A5 activity whereas for CYP3A4 ∗ 22 , some isoenzyme activity remains.…”

Section: Discussionmentioning

confidence: 99%

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Tacrolimus Updated Guidelines through popPK Modeling: How to Benefit More from CYP3A Pre-emptive Genotyping Prior to Kidney Transplantation

et al. 2017

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Tacrolimus (Tac) is a profoundly effective immunosuppressant that reduces the risk of rejection after solid organ transplantation. However, its use is hampered by its narrow therapeutic window along with its highly variable pharmacological (pharmacokinetic [PK] and pharmacodynamic [PD]) profile. Part of this variability is explained by genetic polymorphisms affecting the metabolic pathway. The integration of CYP3A4 and CY3A5 genotype in tacrolimus population-based PK (PopPK) modeling approaches has been proven to accurately predict the dose requirement to reach the therapeutic window. The objective of the present study was to develop an accurate PopPK model in a cohort of 59 kidney transplant patients to deliver this information to clinicians in a clear and actionable manner. We conducted a non-parametric non-linear effects PopPK modeling analysis in Pmetrics®. Patients were genotyped for the CYP3A4∗22 and CYP3A5∗3 alleles and were classified into 3 different categories [poor-metabolizers (PM), Intermediate-metabolizers (IM) or extensive-metabolizers (EM)]. A one-compartment model with double gamma absorption route described very accurately the tacrolimus PK. In covariate analysis, only CYP3A genotype was retained in the final model (Δ-2LL = -73). Our model estimated that tacrolimus concentrations were 33% IC95%[20–26%], 41% IC95%[36–45%] lower in CYP3A IM and EM when compared to PM, respectively. Virtually, we proved that defining different starting doses for PM, IM and EM would be beneficial by ensuring better probability of target concentrations attainment allowing us to define new dosage recommendations according to patient CYP3A genetic profile.

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Section: Discussionmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 99%

Tacrolimus Updated Guidelines through popPK Modeling: How to Benefit More from CYP3A Pre-emptive Genotyping Prior to Kidney Transplantation

et al. 2017

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“…46 In another study of 24 adult Native American kidney transplant recipients, CYP3A5*3 had a higher AF (0.94). 7 CYP3A5*3 is the most-studied CYP3A5 variant in association with tacrolimus and has been evaluated in Europeans, 18,21,[47][48][49][50][51][52] African Americans, 5,24,35,53 Asians, 52,[54][55][56][57][58][59][60] and Native Americans. Allele Frequency…”

Section: Discussionmentioning

confidence: 99%

Tacrolimus troughs and genetic determinants of metabolism in kidney transplant recipients: A comparison of four ancestry groups

Mohamed

Schladt

Guan

et al. 2019

American Journal of Transplantation

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Tacrolimus trough and dose requirements vary dramatically between individuals ofEuropean and African American ancestry. These differences are less well described in other populations. We conducted an observational, prospective, multicenter study from which 2595 kidney transplant recipients of European, African, Native American, and Asian ancestry were studied for tacrolimus trough, doses, and genetic determinants of metabolism. We studied the well-known variants and conducted a CYP3A4/5 gene-wide analysis to identify new variants. Daily doses, and dose-normalized troughs were significantly different between the four groups (P < .001). CYP3A5*3 (rs776746) was associated with higher dose-normalized tacrolimus troughs in all groups but occurred at different allele frequencies and had differing effect sizes. The CYP3A5*6 (rs10264272) and *7 (rs413003343) variants were only present in African Americans. CYP3A4*22 (rs35599367) was not found in any of the Asian ancestry samples. We identified seven suggestive variants in the CYP3A4/5 genes associated with dose-normalized troughs in Native Americans (P = 1.1 × 10 −5 -8.8 × 10 −6 ) and

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“…However, the goal of this study was not to identify all the factors related to variability but to study if variability in trough concentration and dose adversely affects transplant outcomes. Lastly, our study did not consider rarer genetic variants, such as CYP3A4*22 or POR*28, which have been shown to influence TAC metabolism to a lesser extent …”

Section: Discussionmentioning

confidence: 99%

“…Genetic factors are also well‐known to account for TAC pharmacokinetics differences between patients and several single‐nucleotide polymorphisms (SNPs) have been associated with TAC troughs, including CYP3A5*3, CYP3A5*6, CYP3A5*7, CYP3A4*22, and possibly POR*28 . CYP3A5*3, *6, and *7 variants are loss‐of‐function alleles and significantly reduce the metabolic clearance of TAC .…”

Section: Introductionmentioning

confidence: 99%

Tacrolimus trough and dose intra‐patient variability and CYP3A5 genotype: Effects on acute rejection and graft failure in European American and African American kidney transplant recipients

Seibert

Schladt

et al. 2018

Clinical Transplantation

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Background: Suboptimal immunosuppression after kidney transplantation contributes to toxicity and loss of efficacy. Little is known regarding the impact of intra-patient variability of tacrolimus (TAC) doses and troughs in the early post-transplant period or the influence of genetic variants on variability. Methods: Coefficients of variation (CV) of TAC troughs and doses of 1226 European American (EA) and 246 African American (AA) adult recipients enrolled in DeKAF Genomics were compared for association with acute rejection and graft failure. Additionally, the influence of recipients’ number of CYP3A5 loss-of-function alleles was assessed. Results: Acute rejection was associated with greater CV of dose in AA (p<0.001) and EA recipients (p=0.012). Graft failure was associated with a greater CV of dose (p=0.022) and trough (p<0.001) in AA, and higher CV of trough (p=0.024) in EA recipients. In EA, CYP3A5 loss-of-function alleles were associated with decreased CV of trough (p=0.0042) and increased CV of dose (p<0.0001). Conclusion: CYP3A5 loss-of-function alleles influence intra-patient TAC trough and dose variability. High variability of TAC dose increases risk of acute rejection. High variability of TAC trough increases risk of graft failure. Early clinical recognition of TAC dose and trough variability may improve patient management and outcomes.

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The genetic polymorphisms of POR28 and CYP3A53 significantly influence the pharmacokinetics of tacrolimus in Chinese renal transplant recipients

Cited by 45 publications

References 0 publications

Tacrolimus Updated Guidelines through popPK Modeling: How to Benefit More from CYP3A Pre-emptive Genotyping Prior to Kidney Transplantation

Tacrolimus Updated Guidelines through popPK Modeling: How to Benefit More from CYP3A Pre-emptive Genotyping Prior to Kidney Transplantation

Tacrolimus troughs and genetic determinants of metabolism in kidney transplant recipients: A comparison of four ancestry groups

Tacrolimus trough and dose intra‐patient variability and CYP3A5 genotype: Effects on acute rejection and graft failure in European American and African American kidney transplant recipients

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