Pattern of CYP3A5 and MDR-1 single-nucleotide polymorphism and its impact on Tacrolimus levels and clinical outcomes in living renal allograft recipient

Abstract

Abstract Introduction Renal transplant is the best form of renal replacement therapy. The most favored immunosuppression includes Tacrolimus, mycophenolate mofetil, and steroids. Tacrolimus has a narrow therapeutic index and requires therapeutic drug monitoring (TDM). However, there is wide variation in tacrolimus level with weight-based fixed dosage regimens. This variability is due to polymorphism of major pathways of metabolism ie CYP3A5 and MDR1 genes. Fast metabolizers require higher dosage and slow metabolizers require lower dosage. Genotype-based dosing strategy may be useful to achieve early therapeutic level and reduce infections and rejections. Methodology One hundred and sixty transplant patients at tertiary care hospitals in India were included in this study from 2016 to 2018. Genetic polymorphism analysis in CYP3A5 and MDR1 genes was carried out at the time of transplant. All patients were given a fixed weight-based dosage of Tacrolimus. Data were analyzed in relation to genotype polymorphism. Results and discussion 69.2% of wild variants of CYP 3A5 (Fast metabolizers) have low initial tacrolimus levels. 51.5% of Homo variants (Slow metabolizers) have high initial tac levels. However, all variants achieve optimum tacrolimus levels at the same time (mean 12.4 days). There were higher number of infections among slow metabolizers. Conclusion A fixed dosing regimen with TDM results in high and low initial tacrolimus levels in slow and fast metabolizers respectively and more infections in slow metabolizers. However, graft rejections being fewer in number, were not different. A larger sample with genotype-based dosing is required to test such a strategy.