Internal Medicine D (Nephrology, Hypertension and Rheumatology), and Interdisciplinary Fabry Center (IFAZ), University Hospital Muenster, Albert-Schweitzer-Campus 1, 48149, Muenster, Germany.
BioDrugs. 2024 Nov;38(6):845-854. doi: 10.1007/s40259-024-00678-x. Epub 2024 Sep 30.
Current recommendations for Fabry disease include α-galactosidase A (AGAL) activity measurements to assess the biochemical response in migalastat-treated patients. Owing to contradictory data from laboratories, we aimed to analyze why AGAL activity measures from dried blood spots (DBS) often fail to detect migalastat-mediated enzymatic activity increases in treated patients.
43 patients with 58 visits under migalastat were consecutively recruited. Enzymatic AGAL activities were measured from DBS and peripheral blood mononuclear cells (PBMCs). Migalastat concentrations in sera were determined using modified serum-mediated inhibition assays to assess C and serum half-life. Results were set in relation to the time of last migalastat intake and blood sampling to assess an optimal timepoint for AGAL activity measures.
DBS-based AGAL activity measurements of 21 (42.0%) amenable patients were below the limit of detection. Serum samples from migalastat-treated patients showed significant AGAL inhibition, depending on the time between migalastat intake and blood sampling (r = 0.8140, p < 0.0001). Migalastat concentrations were determined in serum samples confirming a C at 3 h and a serum half-life of 4 h. At 24 h after intake, migalastat clearance was significantly associated with renal function (r = 0.3135, p = 0.0102). Enzymatic AGAL activities were higher in samples from DBS and PBMCs 24 h after migalastat intake (both p < 0.05).
The optimal time for enzymatic AGAL activity measurement in migalastat-treated patients appears to be 24 h after the last migalastat intake. Since migalastat is a competitive inhibitor of AGAL, enzymatic AGAL activity measurements should be better performed from PBMCs to reduce migalastat-mediated interferences.
目前推荐使用α-半乳糖苷酶 A（AGAL）活性测量来评估米加酶治疗患者的生化反应。由于实验室数据存在矛盾，我们旨在分析为什么从干血斑（DBS）中测量的 AGAL 活性经常无法检测到米加酶治疗患者的酶活性增加。
连续招募了 43 名接受米加酶治疗的患者，共 58 次就诊。从 DBS 和外周血单核细胞（PBMC）中测量酶促 AGAL 活性。使用改良的血清介导抑制测定法来确定血清中的米加酶浓度，以评估 C 和血清半衰期。结果与最后一次米加酶摄入和血液采样的时间相关，以评估 AGAL 活性测量的最佳时间点。
21 名（42.0%）可评估患者的 DBS 基础 AGAL 活性测量值低于检测下限。米加酶治疗患者的血清样本显示出显著的 AGAL 抑制，这取决于米加酶摄入和血液采样之间的时间（r = 0.8140，p < 0.0001）。在血清样本中确定了米加酶浓度，证实 C 在 3 小时，血清半衰期为 4 小时。摄入后 24 小时，米加酶清除率与肾功能显著相关（r = 0.3135，p = 0.0102）。在摄入米加酶后 24 小时，DBS 和 PBMC 样本中的 AGAL 活性更高（均 p < 0.05）。
米加酶治疗患者进行酶促 AGAL 活性测量的最佳时间似乎是最后一次米加酶摄入后 24 小时。由于米加酶是 AGAL 的竞争性抑制剂，因此应更好地从 PBMC 中进行酶促 AGAL 活性测量，以减少米加酶介导的干扰。
