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

Mendrinou, Effrosyni; Mashaly, Mohamed Elsayed; Okily, Amir Mohamed Al; Mohamed, Mohamed Elsayed; Refaie, Ayman Fathi; Elsawy, Essam; Saleh, Hazem Hamed; Sheashaa, Hussein; Patrinos, George P.

doi:10.3389/fphar.2020.01218

Cited by 17 publications

(11 citation statements)

References 23 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: 93%

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: 93%

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

2021

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“…To the best of our knowledge, this is the first study in Egyptian living kidney transplant patients exploring the possible relationship between POR*28, CYP3A5*3 , and CYP3A4*22 on TAC and CYC dose requirements in the early critical phase post-transplantation. In this study, most of the patients were CYP3A5*3 allele carriers (89.2%), this comes in agreement with what was previously reported in recent Egyptian study where 85.3% of renal transplant patients were carriers of CYP3A5*3 allele [25]. Similarly, studies done in other Arabian countries, like Jordan and Tunisia, show that the CYP3A5*3 allele is of high prevalence [26,27].…”

Section: Discussionsupporting

confidence: 92%

Effect of CYP3A422, CYP3A53 and POR*28 genetic polymorphisms on calcineurin inhibitors dose requirements in early phase renal transplant patients

Ebid,

Ismail,

Lotfy

et al. 2023

Pharmacogenetics and Genomics

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Objective This study aimed to investigate the combined effect of CYP3A5*3, CYP3A4*22, and POR*28 genetic polymorphisms on tacrolimus and cyclosporine dose requirements. Methods One hundred thirty renal transplant patients placed on either tacrolimus or cyclosporine were recruited, where the effect of CYP3A5*3, CYP3A4*22, and POR*28 genetic polymorphisms on their dose requirements were studied at days 14, 30, and 90 post-transplantations. Results The POR*28 allele frequency in the studied population was 29.61%. The tacrolimus dose-adjusted trough concentration ratio (C0/D) was significantly lower in the fast metabolizers group (CYP3A5*1/POR*28(CT/TT) carriers) than in the poor metabolizers group (CYP3A5*3/*3/CYP3A4*22 carriers) throughout the study (14, 30, and 90 days) (P = 0.001, <0.001, and 0.003, respectively). Meanwhile, there was no significant effect of this gene combination on cyclosporine C0/D. Conclusion Combining the CYP3A5*3, POR*28, and CYP3A4*22 genotypes can have a significant effect on early tacrolimus dose requirements determination and adjustments. However, it does not have such influence on cyclosporine dose requirements.

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“…To preliminarily disclosed the cause of individual variate of CE, the role of CYP3A5, the most efficient metabolizing enzyme of TAC, and was evaluated. CYP3A5*3 genetic polymorphism is widely regarded as an essential factor to the high individual variability of TAC (Woillard et al, 2017;Brunet et al, 2019;Mendrinou et al, 2020;van Gelder et al, 2020), and pediatric PNS patients with the CYP3A5*1 allele (rapid metabolizer) have lower TAC exposure than those who do not express CYP3A5 (CYP3A5*3/*3, slow metabolizer) (Huang et al, 2019). Meanwhile, the metabolism of TAC is inhibited by CYP inhibitors.…”

Section: Discussionmentioning

confidence: 99%

Impact of Sampling Time Variability on Tacrolimus Dosage Regimen in Pediatric Primary Nephrotic Syndrome: Single-Center, Prospective, Observational Study

et al. 2022

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Background: Tacrolimus (TAC) is an important immunosuppressant for children with primary nephrotic syndrome (PNS). The relationship between sampling time variability in TAC therapeutic drug monitoring and dosage regimen in such children is unknown.Methods: In this single-center, prospective, observational study, we evaluated the sampling time variability, concentration error (CE), relative CE (RCE), and the impact of the sampling time on TAC dosage regimens in 112 PNS children with 188 blood samples. Nominal concentration (Cnom) at 12-h after last TAC dose was simulated based on observed concentration (Cobs) via previously published pharmacokinetic models, then CE and RCE were calculated. Inappropriate dosing adjustments resulting from deviated sampling time were evaluated based on a target Cnom of 5–10 ng/ml.Results: We found that 32 and 68% of samples were respectively collected early (2–180 min) and delayed (4–315 min). Furthermore, 24, 22, 22, and 32% of blood samples were drawn within deviations of ≤0.5, 0.5–1, 1–2, and >2 h, respectively, and 0.3 ng/ml of CE and 6% RCE per hour of deviation occurred. Within a deviation of >2 h, 25% of Cobs might result in inappropriate dosing adjustments. Early and delayed sampling might result in inappropriate dose holding or unnecessary dose increments, respectively, in patients with Cobs ∼ 5 ng/ml.Conclusions: Variable sampling time might lead to inappropriate dosing adjustment in a minority of children with PNS, particularly those with TAC Cobs ∼ 5 ng/ml collected with a deviation of >2 h.

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

Cited by 17 publications

References 23 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

Effect of CYP3A422, CYP3A53 and POR*28 genetic polymorphisms on calcineurin inhibitors dose requirements in early phase renal transplant patients

Impact of Sampling Time Variability on Tacrolimus Dosage Regimen in Pediatric Primary Nephrotic Syndrome: Single-Center, Prospective, Observational Study

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

Cited by 17 publications

References 23 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

Effect of CYP3A4*22, CYP3A5*3 and POR*28 genetic polymorphisms on calcineurin inhibitors dose requirements in early phase renal transplant patients

Impact of Sampling Time Variability on Tacrolimus Dosage Regimen in Pediatric Primary Nephrotic Syndrome: Single-Center, Prospective, Observational Study

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Effect of CYP3A422, CYP3A53 and POR*28 genetic polymorphisms on calcineurin inhibitors dose requirements in early phase renal transplant patients