Lower Dose‐Normalized Tacrolimus Exposure in <i>CYP3A5</i> *6 vs. *3 Loss‐of‐Function Allele Carriers: A Longitudinal Retrospective Real‐World Study in Kidney Transplant Recipients

Pharmacogenomic research has historically focused on individuals of European ancestry, leading to the underrepresentation of genetic variants common in non-European populations. This bias is exemplified by CYP3A5*6, a functionally consequential variant common in individuals of African ancestry (MAF: 11-19%) but virtually absent in Europeans (MAF: 0.15%). We conducted a retrospective, longitudinal cohort study using real-world data from 1,461 adult kidney transplant recipients across 67 countries, analyzing 4,293 dose-normalized 24-hour area-under-the-curve (AUC_0-24) measurements of tacrolimus. Patients with CYP3A5*1/*1 were excluded. Linear mixed-effects models (LME) were used to assess the association between CYP3A5*6 carriage and tacrolimus exposure, adjusting for clinical factors and ancestry using both HLA-based principal components and country of birth. CYP3A5*6 carriers had a 17% lower dose-normalized AUC_0-24 than CYP3A5*3 carriers (P = 0.015). Sensitivity analyses using dose-normalized trough concentrations (C₀) confirmed these findings, with a 20% lower exposure in CYP3A5*6 carriers (P = 0.011). An interval-based analysis demonstrated persistently lower tacrolimus exposure across the first post-transplant year. All CYP3A5*6-containing genotypes showed significantly lower dose-normalized AUC_0-24 compared to CYP3A5*3/*3, the most common genotype in European populations, with the largest reductions observed in CYP3A5*1/*6 (-39%; P < 0.001) and CYP3A5*3/*6 (-18%; P = 0.006). African origin, defined by country of birth, was independently associated with a 23% higher AUC_0-24 (P < 0.001). This is the first study to demonstrate a differential effect on tacrolimus exposure between the CYP3A5*6 and CYP3A5*3 loss-of-function alleles. Our results may help bridge the ethnicity gap, advance the applicability of pharmacogenomic findings, and promote health equity.