Drug-drug interaction between diltiazem and tacrolimus in relation to CYP3A5 genotype status in Chinese pediatric patients with nephrotic range proteinuria: a retrospective study.

BACKGROUND

Tacrolimus is widely used to treat pediatric nephrotic range proteinuria (NRP). Diltiazem, a CYP3A4/5 inhibitor, is often administered with tacrolimus, affecting its pharmacokinetic profile. The impact of this combination on tacrolimus exposure, particularly in CYP3A53 genetic polymorphism, remains unclear in pediatric NRP patients. This study aimed to evaluate the effects of diltiazem on tacrolimus pharmacokinetics, focusing on the CYP3A53 polymorphism.

METHODS

We conducted a retrospective clinical study involving pediatric NRP patients, divided into two groups: those receiving tacrolimus with diltiazem and those receiving tacrolimus alone. Propensity score matching (PSM) was used to balance the baseline characteristics between the groups. We compared daily dose-adjusted trough concentrations (C/D) of tacrolimus in both the original and PSM cohorts. The influence of diltiazem on tacrolimus C/D, stratified by CYP3A5*3 genetic polymorphism, was assessed in a self-controlled case series study.

RESULTS

Before PSM, the tacrolimus C/D in patients taking diltiazem was significantly higher compared to those with tacrolimus alone (75.84 vs. 56.86 ng/mL per mg/kg, = 0.034). This finding persisted after PSM (75.84 vs. 46.93 ng/mL per mg/kg, = 0.028). In the self-controlled case study, tacrolimus C/D elevated about twofold (75.84 vs. 34.76 ng/mL per mg/kg, < 0.001) after diltiazem administration. CYP3A5 expressers () and CYP3A5 non-expressers () experienced a 1.8-fold and 1.3-fold increase in tacrolimus C/D when combined with diltiazem, respectively.

CONCLUSION

Diltiazem significantly increased tacrolimus C/D, with CYP3A53 expressers showing higher elevations than non-expressers among pediatric NRP patients. These findings highlight the importance of personalized tacrolimus therapy based on CYP3A53 genotypes in pediatric patients taking diltiazem.