CYP3A5基因变异对心脏移植后依维莫司维持剂量的影响。

Influence of CYP3A5 genetic variation on everolimus maintenance dosing after cardiac transplantation.

作者信息

Lesche Dorothea, Sigurdardottir Vilborg, Setoud Raschid, Englberger Lars, Fiedler Georg M, Largiadèr Carlo R, Mohacsi Paul, Sistonen Johanna

机构信息

Institute of Clinical Chemistry, University Hospital (Inselspital Bern), University of Bern, Bern, Switzerland.

Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland.

出版信息

Clin Transplant. 2015 Dec;29(12):1213-20. doi: 10.1111/ctr.12653. Epub 2015 Nov 23.

DOI:10.1111/ctr.12653

PMID:26458301

Abstract

BACKGROUND

Everolimus (ERL) has become an alternative to calcineurin inhibitors (CNIs) due to its renal-sparing properties, especially in heart transplant (HTx) recipients with kidney dysfunction. However, ERL dosing is challenging due to its narrow therapeutic window combined with high interindividual pharmacokinetic variability. Our aim was to evaluate the effect of clinical and genetic factors on ERL dosing in a pilot cohort of 37 HTx recipients.

METHODS

Variants in CYP3A5, CYP3A4, CYP2C8, POR, NR1I2, and ABCB1 were genotyped, and clinical data were retrieved from patient charts.

RESULTS

While ERL trough concentration (C0 ) was within the targeted range for most patients, over 30-fold variability in the dose-adjusted ERL C0 was observed. Regression analysis revealed a significant effect of the non-functional CYP3A53 variant on the dose-adjusted ERL C0 (p = 0.031). ERL dose requirement was 0.02 mg/kg/d higher in patients with CYP3A51/3 genotype compared to patients with CYP3A53/*3 to reach the targeted C0 (p = 0.041). ERL therapy substantially improved estimated glomerular filtration rate (28.6 ± 6.6 mL/min/1.73 m(2)) in patients with baseline kidney dysfunction.

CONCLUSION

Everolimus pharmacokinetics in HTx recipients is highly variable. Our preliminary data on patients on a CNI-free therapy regimen suggest that CYP3A5 genetic variation may contribute to this variability.

摘要

背景

依维莫司（ERL）因其肾脏保护特性已成为钙调神经磷酸酶抑制剂（CNIs）的替代药物，尤其适用于肾功能不全的心脏移植（HTx）受者。然而，由于其治疗窗狭窄且个体间药代动力学变异性高，依维莫司的给药具有挑战性。我们的目的是评估临床和遗传因素对37名心脏移植受者的试点队列中依维莫司给药的影响。

方法

对CYP3A5、CYP3A4、CYP2C8、POR、NR1I2和ABCB1的变体进行基因分型，并从患者病历中检索临床数据。

结果

虽然大多数患者的依维莫司谷浓度（C0）在目标范围内，但观察到剂量调整后的依维莫司C0存在超过30倍的变异性。回归分析显示，无功能的CYP3A53变体对剂量调整后的依维莫司C0有显著影响（p = 0.031）。与CYP3A53/3基因型的患者相比，CYP3A51/*3基因型的患者达到目标C0所需的依维莫司剂量高0.02 mg/kg/d（p = 0.041）。依维莫司治疗显著改善了基线肾功能不全患者的估计肾小球滤过率（28.6±6.6 mL/min/1.73 m²）。