Abstract Objectives Cytochrome P450 3A5 (CYP3A5) gene polymorphisms affect tacrolimus pharmacokinetics. However, their impact on the clinical management of systemic lupus erythematosus (SLE) remains unclear. This study aims to investigate the influence of CYP3A5 gene polymorphisms on pharmacokinetics of tacrolimus and clinical outcomes in patients with SLE. Methods We first analyzed the time-averaged tacrolimus trough concentration-to-dose (C/D) ratio according to CYP3A5 genotype in 114 SLE patients from the Kyoto Lupus Cohort. Second, we retrospectively evaluated impacts of CYP3A5 polymorphisms on tacrolimus concentrations and clinical outcomes over 12 months in 78 patients newly initiating tacrolimus for SLE. Results The time-averaged tacrolimus C/D ratio was 1.6-fold higher in CYP3A5 non-expressers (*3/*3) compared with expressers (*1/*1, *1/*3). A critical therapeutic gap was observed in the early phase: at one month, expressers received higher doses than non-expressers (expressers vs non-expressers, 2.4 mg vs 1.9 mg, p= 0.03), yet their blood concentrations remained paradoxically lower (3.2 ng/ml vs 4.1 ng/ml, p= 0.04). Dose adjustments eventually led to comparable concentrations (∼4.8 ng/ml) and clinical improvements (reduced SLEDAI-2K and prednisolone sparing) by 12 months. Decline of renal function was predominantly driven by age and baseline renal function rather than CYP3A5 genotype. Conclusion CYP3A5 non-expresser genotype increases tacrolimus concentrations in SLE. Initial tacrolimus dosing without considering CYP3A5 status leads to a significant therapeutic lag in expressers. Pre-treatment genotyping is essential to bridge this gap, ensuring rapid achievement of target concentrations and optimizing the efficiency of SLE management from the outset.
Tsuji et al. (2026) studied this question.