CYP3A5 POLYMORPHISM AND ITS INFLUENCE ON OUTCOMES IN RENAL TRANSPLANT RECIPIENTS- A SINGLE CENTRE PROSPECTIVE OBSERVATIONAL STUDY

Introduction:

The clinical use of tacrolimus is complicated by its considerable toxicity, narrow therapeutic window, and high inter-individual pharmacokinetic variability. This variability is largely attributed to genetic polymorphisms in the cytochrome P 450 (CYP) 3A5, the major enzyme responsible for tacrolimus metabolism. Individuals with the CYP3A5*1 allele, either homozygous (*1/*1) or heterozygous (*1/*3) metabolise tacrolimus rapidly, while those with the (*3/*3) genotype are poor metabolisers. The clinical use of tacrolimus is complicated by its considerable toxicity, narrow therapeutic window, and high inter-individual pharmacokinetic variability. This variability is largely attributed to genetic polymorphisms in the cytochrome P 450 (CYP) 3A5, the major enzyme responsible for tacrolimus metabolism. Individuals with the CYP3A5*1 allele, either homozygous (*1/*1) or heterozygous (*1/*3) metabolise tacrolimus rapidly, while those with the (*3/*3) genotype are poor metabolisers.

Methods:

In this single-centre prospective study from August 2021 to June 2024, 86 renal allograft recipients were analysed excluding those patients who died or experienced graft loss within first 3 months. Subjects were categorized into extensive (*1/*1), intermediate (*1/*3), and poor (*3/*3) metabolisers based on PCR genotyping. All received 0.1mg/kg/day dose of tacrolimus on day 0 of transplant and then the levels were modified according to subsequent trough tacrolimus levels (C0) measured using CLIA. These groups were analysed for differences in C0/D tacrolimus trough levels at 1 and 3 months and development of infections, graft rejection, PTDM and Hypomagnesemia.

Results:

The majority were intermediate metabolizers 42 (38.37%), followed by poor 33(48.84%) and extensive 14(16.28%) metabolizers. Poor metabolizers had significantly higher C0/D tacrolimus levels at one and three months. Extensive metabolizers (63.6%) more frequently used enzyme inhibitors like diltiazem and ketoconazole. PTDM prevalence was highest among poor metabolizers (63.64%) [Fig 1], who also exhibited the highest rates of hypomagnesemia (48.28%) and infection [Fig 1]. Frequency of rejection episodes including ABMR, ACMR and borderline ACMR were most common in extensive metabolizers (40%) [Fig 2].

Conclusions:

Genotype-guided dosing can help achieve early target tacrolimus levels, reducing   toxicity and complications while highlighting the prevalence and impact of different CYP3A5 metaboliser types.

I have no potential conflict of interest to disclose.

I used generative AI and AI-assisted technologies in the writing process.
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