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 (C 0 ) 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.