Lower Dose-Normalized Tacrolimus Exposure in CYP3A5*6 vs. *3 Loss-of-Function Allele Carriers: A Longitudinal...

Area of Science:

• Pharmacogenomics
• Transplantation Medicine
• Clinical Pharmacology

Background:

• Pharmacogenomic research historically underrepresents non-European populations.
• The CYP3A5*6 variant is common in African ancestry but rare in Europeans.
• Tacrolimus dosing is influenced by genetic variations in CYP3A5.

Purpose of the Study:

• To investigate the impact of CYP3A5*6 carriage on tacrolimus exposure in kidney transplant recipients.
• To address the underrepresentation of genetic variants in pharmacogenomic studies.
• To explore ethnic differences in drug response.

Main Methods:

• Retrospective, longitudinal cohort study of 1,461 kidney transplant recipients across 67 countries.
• Analysis of 4,293 dose-normalized tacrolimus 24-hour area-under-the-curve (AUC0-24) measurements.
• Linear mixed-effects models adjusted for clinical factors and ancestry (HLA-based PCs, country of birth).

Main Results:

• CYP3A5*6 carriers exhibited a 17% lower dose-normalized tacrolimus AUC0-24 compared to CYP3A5*3 carriers (P=0.015).
• Sensitivity analyses confirmed lower exposure (20% lower C0; P=0.011) persisting throughout the first post-transplant year.
• African origin was independently associated with a 23% higher tacrolimus AUC0-24 (P<0.001).

Conclusions:

• This study is the first to show differential tacrolimus exposure effects between CYP3A5*6 and CYP3A5*3 loss-of-function alleles.
• Findings highlight the clinical significance of CYP3A5*6 and its impact on tacrolimus pharmacokinetics.
• Results contribute to bridging the ethnicity gap in pharmacogenomics and advancing health equity.