Introduction:
The introduction of CNI led to a paradigm shift in outcomes following kidney transplantation. However, Tacrolimus has a narrow therapeutic index with variable pharmacokinetics. CYP3A5 plays an important role for the same with expressors of functional allele (CYP3A5 *1/*1 and *1/*3) having higher dose requirement to achieve desired trough level, compared to non expressors (CYP3A5 *3/*3).Fast and Intermediate metabolizers have at least one functional allele (*1) and are also called expressors whereas poor metabolizers have homozygous nonfunctional allele (*3). Pharmacogenomics allows for a more tailored approach, and in our study, we study the effect of CYP3A5 on pharmacokinetics of tacrolimus in Indian renal transplant recipients, for which there is limited data.
Methods:
We conducted a prospective observational study over 1 year in Manipal Hospital Bangalore. A total of 41 live renal transplant recipients were recruited. Polymorphism in CYP3A5 was detected by targeted gene sequencing and Sentieon haplotype caller was used to identify variants which are relevant to the clinical indication. Patients were divided into extensive, intermediate or poor metabolizers based on genotype (CYP3A5 *1/*1, *1/*3 and *3/*3 respectively).They were started on conventional weight-based dosing. Tacrolimus trough levels were noted at 1 week, 1 month and 3 months. Concentration:Dose (in mg/kg/day) ratio (C:D) was calculated at these points of time. C:D ratio was used to assess and compare pharmacokinetics across all genotypes /metabolizer status.
Results:
Out of 41 patients ,85.3% were male and 51% of patients were under the age of 40. Hypertension was the most common comorbidity seen. IgA nephropathy was the most common native kidney disease, followed by Diabetic Nephropathy. Parents were the most common donors. Induction was used in 87.8% of cases – ATG being the most common agent used. No patient had delayed graft function.
Expressors formed 56% of the population. However, the most common metabolizer status was poor metabolizer at 43.9% and extensive metabolizers with 19.5% was the least common.
Tacrolimus was started on conventional weight-based dosing. Tacrolimus trough achieved at 1 week was largely suboptimal but was highest among poor metabolizers and least among extensive. Tacrolimus levels across different metabolizers was found to be significant at 1 week and 1 month (p=0.001, p=0.04), however there was no significance seen at 3 months (p=0.89). C:D Ratio was highest in poor metabolizers and least in extensive metabolizers across all time periods and was statistically significant. C:D ratio was also statistically significant within each metabolizer status at 1 week, 1 month and 3 months.
Our study had shown a difference in creatinine at all time points across different metabolizer status. 31% of the patients were biopsied and most common finding in biopsy was acute tubular injury. Across metabolizers, extensive metabolizers were most frequently biopsied (50%) and 50% of the biopsies showed rejection.
Conclusions:
Our study shows that CYP3A5 genotype has a strong impact on tacrolimus trough level achieved, especially in early part of transplant. Poor metabolizers / Non expressors have higher C:D ratio than expressors. Genotypic based dosing strategy could help in quickly achieving tacrolimus trough level especially for fast and intermediate metabolizers.
I have no potential conflict of interest to disclose.
I did not use generative AI and AI-assisted technologies in the writing process.