AUTHOR=Yang Qiaoling , Wang Yan , Wang Xuebin , Wang Ping , Tan Boyu , Li Yijun , Sun Huajun , Huang Wenyan , Liu Hongxia 

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

JOURNAL=Frontiers in Pharmacology

VOLUME=15

YEAR=2024

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2024.1463595

DOI=10.3389/fphar.2024.1463595

ISSN=1663-9812

ABSTRACT=<sec><title>Background</title><p>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 CYP3A5*3 genetic polymorphism, remains unclear in pediatric NRP patients. This study aimed to evaluate the effects of diltiazem on tacrolimus pharmacokinetics, focusing on the CYP3A5*3 polymorphism.</p></sec><sec><title>Methods</title><p>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<sub>0</sub>/D) of tacrolimus in both the original and PSM cohorts. The influence of diltiazem on tacrolimus C<sub>0</sub>/D, stratified by CYP3A5*3 genetic polymorphism, was assessed in a self-controlled case series study.</p></sec><sec><title>Results</title><p>Before PSM, the tacrolimus C<sub>0</sub>/D in patients taking diltiazem was significantly higher compared to those with tacrolimus alone (75.84 vs. 56.86 ng/mL per mg/kg, <italic>P</italic> = 0.034). This finding persisted after PSM (75.84 vs. 46.93 ng/mL per mg/kg, <italic>P</italic>= 0.028). In the self-controlled case study, tacrolimus C<sub>0</sub>/D elevated about twofold (75.84 vs. 34.76 ng/mL per mg/kg, <italic>P</italic> &lt; 0.001) after diltiazem administration. CYP3A5 expressers (<italic>CYP3A5*1/*1 and *1/*3</italic>) and CYP3A5 non-expressers (<italic>CYP3A5*3/*3</italic>) experienced a 1.8-fold and 1.3-fold increase in tacrolimus C<sub>0</sub>/D when combined with diltiazem, respectively.</p></sec><sec><title>Conclusion</title><p>Diltiazem significantly increased tacrolimus C<sub>0</sub>/D, with CYP3A5*3 expressers showing higher elevations than non-expressers among pediatric NRP patients. These findings highlight the importance of personalized tacrolimus therapy based on CYP3A5*3 genotypes in pediatric patients taking diltiazem.</p></sec>