Diltiazem on tacrolimus exposure and dose sparing in Chinese pediatric primary nephrotic syndrome: impact of CYP3A4, CYP
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PHARMACOKINETICS AND DISPOSITION
Diltiazem on tacrolimus exposure and dose sparing in Chinese pediatric primary nephrotic syndrome: impact of CYP3A4, CYP3A5, ABCB1, and SLCO1B3 polymorphisms Junyan Wang 1 & Lingfei Huang 1 & Peng Gao 1 & Yan Hu 1 & Yinghua Ni 1 & Zhengyi Zhu 1 & Liwen Zhang 1 & Jufei Yang 1 & Huifen Zhang 1 & Luo Fang 1 Received: 20 February 2020 / Accepted: 11 August 2020 # Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract 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 (C0) were retrospectively collected. The impacts of diltiazem on tacrolimus dose-adjusted C0 (C0/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 C0/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 C0/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. Keywords Tacrolimus . Diltiazem . Drug-drug interaction . Polymorphisms . Dose sparing . Primary nephrotic syndrome
Introduction Tacrolimus is a widely used immunosuppressant for the treatment of rejection in transplantation patients [1] and primary nephrotic syndrome (PNS) [2–4]. For the long-term strategy of tacrolimus, it is considered to be costly; therefore, diltiazem, a calcium channel blocker initially for treating postJunyan Wang and Lingfei Huang contributed equally to this work. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00228-020-02977-y) contains supplementary material, which is available to authorized users. * Huifen Zhang [email protected] * Luo Fang [email protected] 1
Department of Pharmacy, The Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, Zhejiang Province, China
transplant hypertension [5–7], was developed as a costsaving agent by elevating tacrolimus exposure. Combination of diltiazem could significantly increase tacrolimus trough concentration (C0) by 50–100%, resulting in tacrolimus dose reduction and cost-saving in renal transplant recipients [8]. For the dual role of tacrolimus-sparing and antihypertensive effects, concomitant diltiazem is recommended for the renal transplant recipients [9]. Recent
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