The influence of <i>CYP3A5</i> genotype on tacrolimus pharmacokinetics in patients with SLE

OBJECTIVES: Cytochrome P450 3A5 (CYP3A5) gene polymorphisms affect tacrolimus (TAC) pharmacokinetics. However, their impact on the clinical management of SLE remains unclear. This study aims to investigate the influence of CYP3A5 gene polymorphisms on pharmacokinetics of TAC and clinical outcomes in patients with SLE. METHODS: We first analysed the time-averaged TAC 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 TAC concentrations and clinical outcomes over 12 months in 78 patients newly initiating TAC for SLE. RESULTS: The time-averaged TAC 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 1 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 TAC concentrations in SLE. Initial TAC 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.