Diltiazem on tacrolimus exposure and dose sparing in Chinese pediatric primary nephrotic syndrome: impact of CYP3A4, CYP3A5, ABCB1, and SLCO1B3 polymorphisms

Purpose To evaluate the role of diltiazem on tacrolimus sparing in pediatric primary nephrotic syndrome (PNS) and its relation to CYP3A4, CYP3A5, ABCB1, and SLCO1B3 polymorphisms. Methods The PNS children treated with tacrolimus and with steady-state trough concentration (C 0 ) were retrospectively collected. The impacts of diltiazem on tacrolimus dose-adjusted C 0 (C 0 /D), target concentration achievement, and required dose were evaluated. Meanwhile, the relationship between the polymorphisms (including CYP3A4*1G , CYP3A5*3 , ABCB1-C3435T , and SCLO1B3 ) and dose-sparing effect were investigated. Results A total of 71 children with 535 concentrations, including 16 children with concomitant diltiazem, were involved. Significantly increased C 0 /D (94.0 vs 83.8 ng/mL per mg/kg, p = 0.038) and lower required daily dose of tacrolimus (0.056 vs 0.064 mg/kg, p = 0.003) were observed in patients co-administered with diltiazem. Subpopulation carrying CYP3A4*1G , CYP3A5*1 , ABCB1-3435TT , or SLCO1B3-699AA was presented with enhanced increment in tacrolimus C 0 /D by 38.8–102.9%. Conclusion Moderate effect of diltiazem on tacrolimus sparing, which might relate to the polymorphisms of CYP3A4, CYP3A5, ABCB1, and SLCO1B3, was documented.