Department of Clinical Pharmacy, School of Pharmacy, Fudan University.
Departments of Medical Oncology and.
Ther Drug Monit. 2019 Oct;41(5):582-590. doi: 10.1097/FTD.0000000000000642.
As the first-line treatment of gastrointestinal stromal tumor (GIST), the pharmacokinetic and pharmacodynamic of imatinib (IM) were characterized by marked interindividual variability. Pharmacogenetics of IM involved metabolic enzymes and transporters have been extensively reported, but the results remained inconsistent. This study investigated the effect of genetic variants in hepatocyte nuclear factor 4 alpha (HNF4α, encoded by gene NR2A1), a pivotal transcriptional regulator of drug disposition genes, on dose-adjusted IM-free plasma levels and related adverse reactions in Chinese GIST patients.
Five common polymorphisms of NR2A1 (rs3818247, rs1884613, rs2071197, rs2425640, and rs736824) were genotyped in 70 Chinese GIST patients who had been administered IM 300-600 mg/d. The free IM trough plasma levels were determined based on a method of ultrafiltration coupled with high performance liquid chromatography-tandem mass spectrometry.
There were wide interpatient variations in free plasma levels of IM (range, 9.50-67.50 ng/mL), in which significant sex differences were observed (P < 0.01). The dose-adjusted IM-free plasma levels showed a significant negative correlation with body surface area (r = -0.302, P = 0.012). Although there were no significant effects of NR2A1 polymorphisms on dose-adjusted IM-free plasma levels among the study population, polymorphism in rs736824 was found to be significantly associated with dose-adjusted IM-free plasma levels in male subjects (P = 0.031). For the IM-related adverse reaction, polymorphisms in rs3818247 were found to be significantly associated with periorbital edema (P = 0.032). In addition, no significant correlations were found between IM-free plasma levels and IM-related adverse reactions, except for the correlation of IM-free plasma levels with periorbital edema among male patients (P = 0.013).
The research demonstrated that NR2A1 polymorphisms may act as contributors of IM pharmacokinetics and responses in Chinese GIST patients. This represents an attractive opportunity for IM therapy optimization, worth testing in clinical trials.
伊马替尼（IM）作为胃肠道间质瘤（GIST）的一线治疗药物，其药代动力学和药效动力学具有明显的个体间差异。涉及代谢酶和转运体的 IM 药物遗传学已被广泛报道，但结果仍不一致。本研究旨在探讨核因子 4 阿尔法（HNF4α，由基因 NR2A1 编码）的遗传变异对中国 GIST 患者 IM 免费用药后血浆水平和相关不良反应的影响，HNF4α 是药物处置基因的关键转录调节剂。
对 70 例接受 IM 300-600mg/d 治疗的中国 GIST 患者进行 NR2A1 基因的 5 个常见多态性（rs3818247、rs1884613、rs2071197、rs2425640 和 rs736824）的基因分型。采用超滤结合高效液相色谱-串联质谱法测定 IM 游离谷浓度。
IM 游离血浆水平的个体间差异较大（范围 9.50-67.50ng/ml），且存在显著的性别差异（P < 0.01）。剂量调整后的 IM 无药血浆水平与体表面积呈显著负相关（r=-0.302，P=0.012）。尽管 NR2A1 多态性在研究人群中对剂量调整后的 IM 无药血浆水平没有显著影响，但在男性中发现 rs736824 多态性与剂量调整后的 IM 无药血浆水平显著相关（P=0.031）。对于 IM 相关不良反应，rs3818247 多态性与眶周水肿显著相关（P=0.032）。此外，IM 无药血浆水平与 IM 相关不良反应之间除了男性患者的 IM 无药血浆水平与眶周水肿之间的相关性（P=0.013）外，没有发现其他相关性。
本研究表明，NR2A1 多态性可能是中国 GIST 患者 IM 药代动力学和反应的影响因素。这为 IM 治疗优化提供了一个有吸引力的机会，值得在临床试验中进一步验证。
