Dosing algorithm for Tacrolimus in Tunisian Kidney transplant patients: Effect of CYP 3A4*1B and CYP3A4*22 polymorphisms

Ben-Fredj, Nadia; Hannachi, Ibtissem; Chadli, Zohra; Ben-Romdhane, Haifa; Boughattas, Naceur A.; Ben-Fadhel, Najah; Aouam, Karim

doi:10.1016/j.taap.2020.115245

Cited by 9 publications

(19 citation statements)

References 41 publications

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“…Table 2 summarizes the impact of exogenously administered IL-2 inhibitors (basiliximab, daclizumab). 20-22 Basiliximab’s impact on CYP3A4 was considered in 2 studies using cyclosporin and tacrolimus as probes. 20,21 The first study is a retrospective analysis of pediatric renal transplant patients and showed, even in light of a 7% dose reduction of cyclosporin, that there was a 13% increase in trough level in the treatment group 10 days after the basiliximab dose.…”

Section: Data Synthesismentioning

confidence: 99%

“…20-22 Basiliximab’s impact on CYP3A4 was considered in 2 studies using cyclosporin and tacrolimus as probes. 20,21 The first study is a retrospective analysis of pediatric renal transplant patients and showed, even in light of a 7% dose reduction of cyclosporin, that there was a 13% increase in trough level in the treatment group 10 days after the basiliximab dose. 20 Continuing on to days 28 to 50, 87.5% of patients receiving basiliximab had blood cyclosporin concentrations <170 µg/L versus only 20% of patients without treatment.…”

Section: Data Synthesismentioning

confidence: 99%

“…20 Conversely, a cross-sectional study analyzing 685 samples from 102 kidney transplant patients showed that there was no change in trough tacrolimus concentration 4 days after basiliximab administration. 21 Comparing these 2 studies, the short duration of basiliximab before assessing the interaction in the second study may be important because more appreciable results in the first study took several weeks to manifest. 20,21 More data looking at longer therapy is needed to further investigate basiliximab’s impact on the CYP enzyme system.…”

Section: Data Synthesismentioning

confidence: 99%

“…21 Comparing these 2 studies, the short duration of basiliximab before assessing the interaction in the second study may be important because more appreciable results in the first study took several weeks to manifest. 20,21 More data looking at longer therapy is needed to further investigate basiliximab’s impact on the CYP enzyme system.…”

Section: Data Synthesismentioning

confidence: 99%

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Impact of Interferons and Biological Drug Inhibitors of IL-2 and IL-6 on Small-Molecule Drug Metabolism Through the Cytochrome P450 System

2021

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Objective: Assess the impact of interferons and interleukin (IL)-2 and IL-6 inhibitors on cytochrome P450 (CYP) drug metabolism in human subjects. Data Sources: PubMed search from 1980 to March 31, 2021, limited to human subjects and English language via search strategy: (biological drug names) [AND] (cytochrome [OR] CYP metabolism). Study Selection and Data Extraction: Narrative review of human studies assessing biological drugs in select classes that affect CYP drug metabolism. Data Synthesis: Exogenous interferons suppress CYP1A2 (theophylline, caffeine, antipyrone) clearance by 20% to 49% in patients; have minimal impact on CYP3A4 (midazolam and dapsone), CYP2C9 (tolbutamide), or CYP2C19 (mephenytoin) metabolism; and increase CYP2D6 (debrisoquine, dextromethorphan) metabolism. Biological IL-2 inhibitors (basiliximab, daclizumab) have no effect on metabolism via CYP1A2 (caffeine), CYP2C9 (s-warfarin), CYP2C19 (omeprazole), CYP2D6 (dextromethorphan), and CYP3A4 (midazolam, tacrolimus) but may enhance CYP3A4 (cyclosporin) metabolism over time. IL-6 inhibitors (sirukumab, tocilizumab, sarilumab) significantly enhance metabolism via CYP2C9 (s-warfarin), CYP2C19 (omeprazole), and CYP3A4 (simvastatin, midazolam) and reduce metabolism via CYP1A2 (caffeine). Relevance to Patient Care and Clinical Practice: Patients using interferons, IL-2, or IL-6 blocking drugs at steady state with CYP substrates could have altered drug metabolism and experience adverse events. With interferons and biological anti-inflammatory drugs, some isoenzymes will be inhibited, whereas others will be enhanced, and the magnitude of the effect can sometimes be significant. In clinical practice, clinicians may consider these metabolic changes as an additive effect to a patient’s entire disease and medication profile when determining risk/benefit of treatment. Conclusions: Interferon therapy or inflammatory suppression via IL-2 or IL-6 can alter steady-state concentrations of CYP-metabolized small-molecule drugs.

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Section: Data Synthesismentioning

confidence: 99%

Section: Data Synthesismentioning

confidence: 99%

Section: Data Synthesismentioning

confidence: 99%

Section: Data Synthesismentioning

confidence: 99%

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Impact of Interferons and Biological Drug Inhibitors of IL-2 and IL-6 on Small-Molecule Drug Metabolism Through the Cytochrome P450 System

2021

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“…Due to the narrow therapeutic window of tacrolimus, therapeutic drug monitoring (TDM) is essential to maintain adequate blood concentrations to prevent graft rejection due to inadequate immunosuppression and toxicity due to higher drug levels ( Brunet et al, 2019 ). Despite the advances in medicine, attaining and maintaining the optimal therapeutic range of tacrolimus specific to different post-transplant time points remains a challenge ( Herrero et al, 2013 ; Ben-Fredj et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

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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Synergistic Effect of Cytochrome P450 Family 3 Subfamily A Member 5 (CYP3A5) Genetic Variants in Tacrolimus Dose Determination in Indian Renal Transplant Patients

Hemani,

Chauhan,

Srivastava

et al. 2024

ACS Pharmacol. Transl. Sci.

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Tacrolimus (TAC) has a narrow therapeutic index and shows interindividual variabilities in its blood concentration. Although guidelines recommend a genetic variant (rs776746) to determine the optimized TAC dose, discrepancies in accuracy have been noted. Therefore, studying other variants of CYP3A5 may improve the accuracy of the TAC dose. Clinical exome sequencing (CES) was performed in 219 renal transplant patients. The SNPs of CYP3A5 covered by CES were recorded. The TAC blood trough concentration/dose (C 0/D) was calculated on day 7 and months 1, 3, 6, and 12 of post-transplantation, and association with CYP3A5 genotypes was studied. Further, biopsy-proven rejection and pathological events were analyzed for their association with CYP3A5 genotypes. Out of 35 variants of CYP3A5 covered in CES, rs776746, rs15524, rs4646449, and rs464645 were significantly associated with the TAC C 0/D on day 7 and months 1, 3, and 6. Further analysis showed that the slow-metabolizing genotypes of all four SNPs synergistically associated with the TAC C 0/D on day 7 and months 1, 3, 6, and 12. The “CC” genotype of rs776746 showed a significant association (RR = 1.613; p = 0.035) with allograft rejection. In addition, cox regression analysis showed that the presence of the “CA” genotype of rs4646453 increased (HR = 7.258; 95% CI = 1.354–38.904) the risk of development of pathological events, respectively. Four variants of CYP3A5 were synergistically associated with the TAC dose determination. In addition, rs776746 and rs4646453 may be associated with allograft rejection and pathological events, respectively.

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Dosing algorithm for Tacrolimus in Tunisian Kidney transplant patients: Effect of CYP 3A41B and CYP3A422 polymorphisms

Cited by 9 publications

References 41 publications

Impact of Interferons and Biological Drug Inhibitors of IL-2 and IL-6 on Small-Molecule Drug Metabolism Through the Cytochrome P450 System

Impact of Interferons and Biological Drug Inhibitors of IL-2 and IL-6 on Small-Molecule Drug Metabolism Through the Cytochrome P450 System

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

Synergistic Effect of Cytochrome P450 Family 3 Subfamily A Member 5 (CYP3A5) Genetic Variants in Tacrolimus Dose Determination in Indian Renal Transplant Patients

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