評估結節硬化症患者 Everolimus 的使用情形和藥物基因體學研究

Abstract

背景: 結節硬化症是一種罕見遺傳疾病，為體染色體顯性遺傳，主要罹病原因為 TSC1 基因 TSC2 基因發生致病變異，使得 mTOR(mammalian target of rapamycin) 路徑活化，導致細胞不正常生長。因此可以使用 m-TOR 抑制劑來治療，抑制腫瘤生長。目前 everolimus 已核可使用在結節硬化症相關的腎血管平滑肌脂肪瘤、腦室管膜下巨細胞星狀細胞瘤及局部型癲癇等。 觀察到在國立臺灣大學醫學院附設醫院暨醫學中心之結節硬化症整合門診的病人，其個體間 everolimus 的藥物血中濃度變化較大，因此想了解影響everolimus 藥物血中濃度的原因及藥物代謝基因之變異是否有影響。 研究方法: 本研究收案結節硬化症門診使用 everolimus 藥物的病人共 75 位，其中只有 11 位病人為早上服用藥物並於早上服藥前抽血，較接近藥物血中谷濃度。並以這 11 位病人利用建立的 pharmacogenomics next generation sequencing panel 來做基因檢測分析，並將結果輔助使用 ALDY 及 IGV 軟體來判斷基因型，以潛在相關的基因 CYP3A4、CYP3A5、CYP2C8 及 ABCB1 進行分析，並探討其可能的影響。 結果: 影響 everolimus 藥物血中濃度的原因有很多，包括服藥順從性、藥物藥物交互作用、抽血時間等。本次研究觀察到帶有 CYP3A5*3 變異之病人與不帶有此變異之病人，其 everolimus 的藥物血中濃度沒有顯著差異。 總結: 這可能是第一個有討論關於 everolimus 用於結節硬化症的藥物基因體學研究，但因收案人數較少及一些方法的限制，未來可能需要其他更進一步的研究與證據，來協助建立更適合個別病人的治療計畫。

Background: Tuberous sclerosis complex (TSC) is a rare disease inherited in an autosomal dominant manner. The primary cause of the disease is pathogenic variants in the TSC1 and TSC2 genes, leading to activation of the mammalian target of rapamycin (mTOR) pathway and abnormal cell growth. Therefore, mTOR inhibitors can be used for treatment to suppress tumor growth. Currently, everolimus has been approved for the treatment of TSC-associated renal angiomyolipomas, subependymal giant cell astrocytomas, and focal seizures. We have observed that there was significant variation in the blood concentrations of everolimus among the outpatients with TSC regularly visiting National Taiwan University Hospital. Thus, the study aimed to understand the factors influencing the blood concentration of everolimus and whether genetic variations in drug- metabolizing genes play a role. Methods: A total of 75 patients with TSC receiving everolimus treatment at the clinic were enrolled, but only 11 patients took everolimus in the morning and had blood drawn also in the morning, which approximates to the trough concentration. Therefore, only these 11 patients underwent genetic test and analysis using the established PGx NGS panel, and the results were further analyzed using ALDY and IGV software to determine the genotypes of the CYP3A4, CYP3A5, CYP2C8, and ABCB1 genes. Results: There are various factors that can influence the blood concentration of everolimus, including medication adherence, drug-drug interactions, and the timing of blood sampling. In this study, it was observed that there was no significant difference in the blood concentration of everolimus between patients with the CYP3A5*3 variant and those without it. Conclusions: This may be the first pharmacogenomic study discussing the use of everolimus in TSC, but due to the small sample size and limitations of certain methods, further research and evidence are needed in the future to help establish more personalized treatment plans for individual patients.