The Multiple Sclerosis Center of Northeastern New York, Latham, NY, USA.
The Multiple Sclerosis Center of Northeastern New York, Latham, NY, USA.
Mult Scler Relat Disord. 2021 Jun;51:102861. doi: 10.1016/j.msard.2021.102861. Epub 2021 Feb 24.
Biomarkers are a useful and reliable measure of disease activity in many fields of medicine. Axonal and glial biomarkers in multiple sclerosis (MS) are being applied more often as technology is improving and becoming increasingly reliable. Nonclinical studies have shown dimethyl fumarate (DMF) to have cytoprotective and anti-inflammatory effects. The purpose of this study is to explore the pharmacokinetics (PK) of DMF (by measuring MMF, the active compound) in serum and cerebrospinal fluid (CSF) as well as relevant biomarker data for patients with secondary progressive MS (pwSPMS) and whether there is objective evidence for neuroprotection in pwSPMS treated with DMF.
Sixteen pwSPMS had serum and cerebrospinal fluid (CSF) evaluation for PK studies levels of MMF at various time points after ingestion of DMF. The CSF biomarkers neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), ubiquitin carboxyo-terminal hydrolase isozyme L1 (UCH-L1) and total tau (T-tau) were measured at baseline, week 6 and week 28 after initiating DMF with a starting dose of 120 mg twice daily for 4 weeks, followed by a maintenance dose of 240 mg twice daily. Clinical correlation of these patients with EDSS and MRI at these same time periods were made with the biomarkers. Four normal human volunteers had CSF studies for biomarkers at baseline.
PK data showed CSF MMF concentration 11% of plasma with Tmax of plasma at 5 hr and Tmax of CSF at 7 hr. Biomarker data showed that CS NfL and to a lesser extent, GFAP, but not UCH-L1 nor T-tau showed relevant changes with clinical data. Some pwSPMS receiving DMF showed clinical improvements in Expanded Disability Status Scale (EDSS). Biomarker changes, but not MRI, correlated with clinical measures in this group of pwSPMS over the observation period.
PK data showed that the Tmax of CSF MMF peaked only 2 hours later than that of plasma with 11% measured in the CSF so that MMF readily crossed the blood brain barrier allowing potential direct penetration into the brain. NfL CSF levels, and to a lesser extent, GFAP CSF levels, showed correlation to disease activity in pwSPMS . These data suggest that DMF may have some benefit in reducing disease activity in pwSPMS if studied for a longer duration and larger well-controlled studies are warranted. DMF was reasonably well tolerated but 3 of the 16 patients did discontinue DMF at 6 weeks due to persistent side effects. NfL appeared to be more clinically relevant biomarker than brain MRI in this this group during the 28-week study period.
生物标志物是医学许多领域中衡量疾病活动的有用且可靠的指标。多发性硬化症（MS）中的轴突和神经胶质生物标志物的应用越来越多，因为技术正在不断提高并变得越来越可靠。非临床研究表明，富马酸二甲酯（DMF）具有细胞保护和抗炎作用。本研究旨在探索继发进展型多发性硬化症（pwSPMS）患者 DMF 的药代动力学（PK）（通过测量 MMF，即活性化合物）在血清和脑脊液（CSF）中的情况，以及相关的生物标志物数据，以及 DMF 治疗 pwSPMS 是否具有神经保护的客观证据。
16 名 pwSPMS 患者在服用 DMF 后不同时间点进行血清和脑脊液（CSF）评估，以检测 MMF 的 PK 水平。在开始使用 DMF 治疗的第 4 周，起始剂量为每日两次 120mg，持续 4 周，然后维持剂量为每日两次 240mg，在第 6 周和第 28 周时测量神经丝轻链（NfL）、神经胶质纤维酸性蛋白（GFAP）、泛素羧基末端水解酶同工酶 L1（UCH-L1）和总 tau（T-tau）等 CSF 生物标志物。在同一时间段内，这些患者的临床相关性与生物标志物的 EDSS 和 MRI 进行了比较。4 名正常志愿者在基线时进行了 CSF 研究以检测生物标志物。
PK 数据显示，CSF 中 MMF 的浓度为血浆的 11%，血浆中的 Tmax 为 5 小时，CSF 中的 Tmax 为 7 小时。生物标志物数据显示，CS 中的 NfL 和在较小程度上 GFAP，但不是 UCH-L1 或 T-tau，与临床数据有相关变化。一些接受 DMF 治疗的 pwSPMS 在扩展残疾状况量表（EDSS）中显示出临床改善。在观察期间，该组 pwSPMS 的生物标志物变化，而不是 MRI，与临床指标相关。
PK 数据显示，CSF 中 MMF 的 Tmax 仅比血浆晚 2 小时达到峰值，其浓度为 11%，表明 MMF 很容易穿过血脑屏障，从而有可能直接穿透大脑。NfL CSF 水平，以及在较小程度上，GFAP CSF 水平，与 pwSPMS 中的疾病活动相关。这些数据表明，DMF 在研究时间更长、对照更好的研究中可能对 pwSPMS 中的疾病活动具有一定的益处。DMF 的耐受性良好，但有 3 名患者在 6 周时因持续的副作用而停止使用 DMF。在 28 周的研究期间，NfL 似乎比脑 MRI 更能反映该组患者的临床相关性生物标志物。
