Influence of CYP3A polymorphisms on tacrolimus pharmacokinetics in kidney transplant recipients

Hannachi, Ibtissem; Chadli, Zohra; Kerkeni, Emna; Kolsi, Abdessalem; Hammouda, M.; Chaabane, Amel; Fredj, Nadia Ben; Touitou, Yvan; Boughattas, Naceur A.; Aouam, Karim

doi:10.1038/s41397-020-00179-4

Cited by 11 publications

(12 citation statements)

References 28 publications

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“…We investigated the contribution of five polymorphisms in three genes involved in the metabolism and transport of tacrolimus to the dose-adjusted tacrolimus concentration at three different time points. Consistent with the results of earlier studies ( Li et al, 2014 ; Khan et al, 2020 ; Mendrinou et al, 2020 ; Hannachi et al, 2021 ), we found a strong association of CYP3A5 *3 polymorphism with tacrolimus C 0 /D at different time points after transplantation ( p < 0.001). Differential expression of CYP3A5 is known to influence the tacrolimus bioavailability in individuals.…”

Section: Discussionsupporting

confidence: 92%

Pharmacogenetics Based Dose Prediction Model for Initial Tacrolimus Dosing in Renal Transplant Recipients

2021

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Tacrolimus, an immunosuppressant used in solid organ transplantation, has a narrow therapeutic index and exhibits inter-individual pharmacokinetic variability. Achieving and maintaining a therapeutic level of the drug by giving appropriate doses is crucial for successful immunosuppression, especially during the initial post-transplant period. We studied the effect of CYP3A5, CYP3A4, and ABCB1 gene polymorphisms on tacrolimus trough concentrations in South Indian renal transplant recipients from Kerala to formulate a genotype-based dosing equation to calculate the required starting daily dose of tacrolimus to be given to each patient to attain optimal initial post-transplant period drug level. We also investigated the effect of these genes on drug-induced adverse effects and rejection episodes and looked into the global distribution of allele frequencies of these polymorphisms. One hundred forty-five renal transplant recipients on a triple immunosuppressive regimen of tacrolimus, mycophenolate mofetil, and steroid were included in this study. Clinical data including tacrolimus daily doses, trough levels (C0) and dose-adjusted tacrolimus trough concentration (C0/D) in blood at three time points (day 6, 6 months, and 1-year post-transplantation), adverse drug effects, rejection episodes, serum creatinine levels, etc., were recorded. The patients were genotyped for CYP3A5*3, CYP3A4*1B, CYP3A4*1G, ABCB1 G2677T, and ABCB1 C3435T polymorphisms by the PCR-RFLP method. We found that CYP3A5*3 polymorphism was the single most strongly associated factor determining the tacrolimus C0/D in blood at all three time points (p < 0.001). Using multiple linear regression, we formulated a simple and easy to compute equation that will help the clinician calculate the starting tacrolimus dose per kg body weight to be administered to a patient to attain optimal initial post-transplant period tacrolimus level. CYP3A5 expressors had an increased chance of rejection than non-expressors (p = 0.028), while non-expressors had an increased risk for new-onset diabetes mellitus after transplantation (NODAT) than expressors (p = 0.018). Genotype-guided initial tacrolimus dosing would help transplant recipients achieve optimal initial post-transplant period tacrolimus levels and thus prevent the adverse effects due to overdose and rejection due to inadequate dose. We observed inter-population differences in allele frequencies of drug metabolizer and transporter genes, emphasizing the importance of formulating population-specific dose prediction models to draw results of clinical relevance.

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Section: Discussionsupporting

confidence: 92%

Pharmacogenetics Based Dose Prediction Model for Initial Tacrolimus Dosing in Renal Transplant Recipients

2021

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“…Hannachi et al showed a significant decrease of TAC C 0 /D in CYP3A4*1B carriers compared to wild-type, also demonstrating a higher C 0 /D ratio in patients with the CYP3A4*22 allele compared to non-carriers [ 50 ].…”

Section: Resultsmentioning

confidence: 99%

Use of Pharmacogenetics to Optimize Immunosuppressant Therapy in Kidney-Transplanted Patients

et al. 2022

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Immunosuppressant drugs (ISDs) are routinely used in clinical practice to maintain organ transplant survival. However, these drugs are characterized by a restricted therapeutic index, a high inter- and intra-individual pharmacokinetic variability, and a series of severe adverse effects. In particular, genetic factors have been estimated to play a role in this variability because of polymorphisms regarding genes encoding for enzymes and transporters involved in the ISDs pharmacokinetic. Several studies showed important correlations between genetic polymorphisms and ISDs blood levels in transplanted patients; therefore, this review aims to summarize the pharmacogenetics of approved ISDs. We used PubMed database to search papers on pharmacogenetics of ISDs in adults or pediatric patients of any gender and ethnicity receiving immunosuppressive therapy after kidney transplantation. We utilized as search term: “cyclosporine or tacrolimus or mycophenolic acid or sirolimus or everolimus and polymorphism and transplant”. Our data showed that polymorphisms in CYP3A5, CYP3A4, ABCB1, and UGT1A9 genes could modify the pharmacokinetics of immunosuppressants, suggesting that patient genotyping could be a helpful strategy to select the ideal ISDs dose for each patient.

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“…It has been reported that some SNPs in CYP3A4 and CYP3A5 genes down-regulate their enzymatic activities, which impact the metabolisms of some drugs, leading to different clinical outcomes (33). For example, two closely linked SNPs, CYP3A4 rs2940574 and CYP3A5 rs776746, have been found to be associated with the metabolism of tacrolimus in kidney transplant patients (34,35). CYP3A5 rs776746 (CYP3A5*3) causes a splicing defect in the CYP3A5 transcript, resulting in significantly lower expression of active CYP3A5 enzyme.…”

Section: Resultsmentioning

confidence: 99%

Evaluating the Impacts of CYP3A41B and CYP3A53 Variations on Pharmacokinetic Behavior and Clinical Outcomes in Multiple Myeloma Patients With Autologous Stem Cell Transplant

Cho

Sborov

Phelps

et al. 2022

Cancer Genomics Proteomics

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Background/Aim: There exists considerably large interpatient variability in pharmacokinetic exposure of high dose melphalan in multiple myeloma patients with hematopoietic stem-cell transplantation. In this study, we aimed to evaluate the potential impacts of CYP3A4*1B (rs2940574) and CYP3A5*3 (rs776746) variations on pharmacokinetic properties of melphalan and clinical outcomes in multiple myeloma (MM) patients. Patients and Methods: Genotypes of CYP3A4*1B (rs2940574) and CYP3A5*3 (rs776746) were determined by validated genespecific real-time PCR (RT-PCR) assays using DNA samples from 108 MM patients; plasma concentrations of melphalan at different time points were quantified using liquid chromatography-tandem mass spectrometry (LC-MS/ΜS).Results: CYP3A4*1B/*1B and CYP3A5*3/*3 carriers appeared to have a short median progression-free survival time and a higher maximum melphalan plasma concentration than non-carriers [792 vs. over 950 days, p=0.08; 9.91 (2.67, 34.03) vs. 8.66 (4.46, 17.61) mg/l, p=0.039]. Conclusion: CYP3A4*1B/*1B and CYP3A5*3/*3 variations might influence melphalan therapy in MM patients through yet-to-be-identified mechanisms.

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Influence of CYP3A polymorphisms on tacrolimus pharmacokinetics in kidney transplant recipients

Cited by 11 publications

References 28 publications

Pharmacogenetics Based Dose Prediction Model for Initial Tacrolimus Dosing in Renal Transplant Recipients

Pharmacogenetics Based Dose Prediction Model for Initial Tacrolimus Dosing in Renal Transplant Recipients

Use of Pharmacogenetics to Optimize Immunosuppressant Therapy in Kidney-Transplanted Patients

Evaluating the Impacts of CYP3A41B and CYP3A53 Variations on Pharmacokinetic Behavior and Clinical Outcomes in Multiple Myeloma Patients With Autologous Stem Cell Transplant

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Influence of CYP3A polymorphisms on tacrolimus pharmacokinetics in kidney transplant recipients

Cited by 11 publications

References 28 publications

Pharmacogenetics Based Dose Prediction Model for Initial Tacrolimus Dosing in Renal Transplant Recipients

Pharmacogenetics Based Dose Prediction Model for Initial Tacrolimus Dosing in Renal Transplant Recipients

Use of Pharmacogenetics to Optimize Immunosuppressant Therapy in Kidney-Transplanted Patients

Evaluating the Impacts of CYP3A4*1B and CYP3A5*3 Variations on Pharmacokinetic Behavior and Clinical Outcomes in Multiple Myeloma Patients With Autologous Stem Cell Transplant

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Evaluating the Impacts of CYP3A41B and CYP3A53 Variations on Pharmacokinetic Behavior and Clinical Outcomes in Multiple Myeloma Patients With Autologous Stem Cell Transplant