The Clinical Impact of the C0/D Ratio and the CYP3A5 Genotype on Outcome in Tacrolimus Treated Kidney Transplant Recipients
Tacrolimus is metabolized by CYP3A4 and CYP3A5 enzymes. Patients expressing CYP3A5 (in Caucasian patients about 15% of the population but more frequent in African Americans and Asians) have a dose requirement that is around 50% higher than non-expressers to reach the target concentration. CYP3A5 exp...
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Frontiers Media S.A.
2020-07-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fphar.2020.01142/full |
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| author | Teun van Gelder Soufian Meziyerh Soufian Meziyerh Jesse J. Swen Aiko P. J. de Vries Aiko P. J. de Vries Dirk Jan A. R. Moes |
| author_facet | Teun van Gelder Soufian Meziyerh Soufian Meziyerh Jesse J. Swen Aiko P. J. de Vries Aiko P. J. de Vries Dirk Jan A. R. Moes |
| author_sort | Teun van Gelder |
| collection | DOAJ |
| description | Tacrolimus is metabolized by CYP3A4 and CYP3A5 enzymes. Patients expressing CYP3A5 (in Caucasian patients about 15% of the population but more frequent in African Americans and Asians) have a dose requirement that is around 50% higher than non-expressers to reach the target concentration. CYP3A5 expressers can be considered fast metabolizers. The trough concentration/dose (C0/D) ratio of tacrolimus has recently been proposed as a prognostic marker for poor outcome after kidney transplantation. Patients with a low C0/D ratio (also referred to as fast metabolizers) seem to have more tacrolimus-related nephrotoxicity, more BK-viremia, and a lower graft survival. At first sight, the expression of CYP3A5 and a low C0/D ratio seem to be overlapping factors, both pointing towards patients in whom a higher tacrolimus dose is needed to reach the tacrolimus target concentration. However, there are important differences, and these differences may explain why the impact of the C0/D ratio on long term outcome is stronger than for CYP3A5 genotype status. Patients with a low C0/D ratio require a high tacrolimus dose and are exposed to high tacrolimus peak concentrations. The higher peak exposure to tacrolimus (and/or its metabolites) may explain the higher incidence of nephrotoxicity, BK-viremia and graft loss. A potential confounder is the concurrent maintenance treatment of corticosteroids, as steroids are sometimes continued in patients at high immunological risk. Steroids induce the metabolism of tacrolimus via pregnane X receptor mediated increased CYP3A4 expression, resulting in lower tacrolimus C0/D ratio in high risk patients. Also non-adherence may result in lower C0/D ratio which is also associated with poor outcome. The C0/D ratio of tacrolimus does seem to identify a group of patients with increased risk of poor outcome after kidney transplantation. Our recommendation is to monitor tacrolimus peak concentrations in these patients, and if these are high then target slightly lower pre-dose concentrations. Another possibility would be to switch to a prolonged release formulation or to dose the drug more frequently, in smaller doses, to avoid high peak concentrations. |
| first_indexed | 2024-12-21T14:41:22Z |
| format | Article |
| id | doaj.art-4e70c9272dca40afaf1f5dcab43680fd |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-12-21T14:41:22Z |
| publishDate | 2020-07-01 |
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| spelling | doaj.art-4e70c9272dca40afaf1f5dcab43680fd2022-12-21T19:00:11ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122020-07-011110.3389/fphar.2020.01142533972The Clinical Impact of the C0/D Ratio and the CYP3A5 Genotype on Outcome in Tacrolimus Treated Kidney Transplant RecipientsTeun van Gelder0Soufian Meziyerh1Soufian Meziyerh2Jesse J. Swen3Aiko P. J. de Vries4Aiko P. J. de Vries5Dirk Jan A. R. Moes6Department of Clinical Pharmacy & Toxicology, Leiden University Medical Center, Leiden, NetherlandsDepartment of Internal Medicine, Division of Nephrology, Leiden University Medical Center, Leiden, NetherlandsLeiden Transplant Center, Leiden University Medical Center, Leiden, NetherlandsDepartment of Clinical Pharmacy & Toxicology, Leiden University Medical Center, Leiden, NetherlandsDepartment of Internal Medicine, Division of Nephrology, Leiden University Medical Center, Leiden, NetherlandsLeiden Transplant Center, Leiden University Medical Center, Leiden, NetherlandsDepartment of Clinical Pharmacy & Toxicology, Leiden University Medical Center, Leiden, NetherlandsTacrolimus is metabolized by CYP3A4 and CYP3A5 enzymes. Patients expressing CYP3A5 (in Caucasian patients about 15% of the population but more frequent in African Americans and Asians) have a dose requirement that is around 50% higher than non-expressers to reach the target concentration. CYP3A5 expressers can be considered fast metabolizers. The trough concentration/dose (C0/D) ratio of tacrolimus has recently been proposed as a prognostic marker for poor outcome after kidney transplantation. Patients with a low C0/D ratio (also referred to as fast metabolizers) seem to have more tacrolimus-related nephrotoxicity, more BK-viremia, and a lower graft survival. At first sight, the expression of CYP3A5 and a low C0/D ratio seem to be overlapping factors, both pointing towards patients in whom a higher tacrolimus dose is needed to reach the tacrolimus target concentration. However, there are important differences, and these differences may explain why the impact of the C0/D ratio on long term outcome is stronger than for CYP3A5 genotype status. Patients with a low C0/D ratio require a high tacrolimus dose and are exposed to high tacrolimus peak concentrations. The higher peak exposure to tacrolimus (and/or its metabolites) may explain the higher incidence of nephrotoxicity, BK-viremia and graft loss. A potential confounder is the concurrent maintenance treatment of corticosteroids, as steroids are sometimes continued in patients at high immunological risk. Steroids induce the metabolism of tacrolimus via pregnane X receptor mediated increased CYP3A4 expression, resulting in lower tacrolimus C0/D ratio in high risk patients. Also non-adherence may result in lower C0/D ratio which is also associated with poor outcome. The C0/D ratio of tacrolimus does seem to identify a group of patients with increased risk of poor outcome after kidney transplantation. Our recommendation is to monitor tacrolimus peak concentrations in these patients, and if these are high then target slightly lower pre-dose concentrations. Another possibility would be to switch to a prolonged release formulation or to dose the drug more frequently, in smaller doses, to avoid high peak concentrations.https://www.frontiersin.org/article/10.3389/fphar.2020.01142/fulltacrolimustransplantationkidneyCYP3A5pharmacogenetics |
| spellingShingle | Teun van Gelder Soufian Meziyerh Soufian Meziyerh Jesse J. Swen Aiko P. J. de Vries Aiko P. J. de Vries Dirk Jan A. R. Moes The Clinical Impact of the C0/D Ratio and the CYP3A5 Genotype on Outcome in Tacrolimus Treated Kidney Transplant Recipients Frontiers in Pharmacology tacrolimus transplantation kidney CYP3A5 pharmacogenetics |
| title | The Clinical Impact of the C0/D Ratio and the CYP3A5 Genotype on Outcome in Tacrolimus Treated Kidney Transplant Recipients |
| title_full | The Clinical Impact of the C0/D Ratio and the CYP3A5 Genotype on Outcome in Tacrolimus Treated Kidney Transplant Recipients |
| title_fullStr | The Clinical Impact of the C0/D Ratio and the CYP3A5 Genotype on Outcome in Tacrolimus Treated Kidney Transplant Recipients |
| title_full_unstemmed | The Clinical Impact of the C0/D Ratio and the CYP3A5 Genotype on Outcome in Tacrolimus Treated Kidney Transplant Recipients |
| title_short | The Clinical Impact of the C0/D Ratio and the CYP3A5 Genotype on Outcome in Tacrolimus Treated Kidney Transplant Recipients |
| title_sort | clinical impact of the c0 d ratio and the cyp3a5 genotype on outcome in tacrolimus treated kidney transplant recipients |
| topic | tacrolimus transplantation kidney CYP3A5 pharmacogenetics |
| url | https://www.frontiersin.org/article/10.3389/fphar.2020.01142/full |
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