Analysis of Concentrations of Monomethyl Fumarate in Patients with Multiple Sclerosis: Result from Routine Health Care

Zuzana Krska Kusnirikova, Ivana Kacirova, Veronika Pesakova, Pavel Hradilek, Hana Brozmanova, Milan Grundmann
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Abstract

Background: Dimethyl fumarate is used to treat patients with relapsing-remitting multiple sclerosis. After ingestion, it is rapidly hydrolyzed to the active primary metabolite monomethyl fumarate.

Objective: The main objective of our study was to analyze serum concentrations of monomethyl fumarate during routine health care in patients with multiple sclerosis treated with a fixed dose of dimethyl fumarate.

Methods: In the pilot cross-sectional study, data from 42 patients treated with dimethyl fumarate at a dose of 240 mg twice daily were collected. Concentrations of the active metabolite monomethyl fumarate were determined at 1-8 h (median, 3 h) or 10-14 h (median, 13 h) after taking the dose. The relationship between monomethyl fumarate concentrations and absolute lymphocyte count was evaluated.

Results: Concentrations of monomethyl fumarate ranged from 2.5-3177.9 μg/L, with most concentrations being undetectable approximately 10 hours after administration. In the 1-8 h (median, 3 h) post-dose subgroup, the concentration/dose ratio ranged widely from 0.04-6.62. The median concentration of monomethyl fumarate in the group with the absolute lymphocyte count <0.8 x 10^9/l was more than four times higher than in the group with the absolute lymphocyte count ≥0.8 x 10^9/l (median 440.1 μg/L versus 98.4 μg/L).

Conclusion: The wide interindividual variability in monomethyl fumarate pharmacokinetics could contribute to the differential response to dimethyl fumarate in multiple sclerosis patients. A nonsignificant but noticeable trend was observed in the relationship of higher serum monomethyl fumarate concentrations to absolute lymphocyte counts.

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多发性硬化症患者富马酸单甲酯浓度分析:常规医疗保健的结果。
背景:富马酸二甲酯用于治疗复发-缓解型多发性硬化症患者。富马酸二甲酯摄入后会迅速水解为活性初级代谢物富马酸单甲酯:我们研究的主要目的是分析接受固定剂量富马酸二甲酯治疗的多发性硬化症患者在日常保健过程中血清中富马酸单甲酯的浓度:在这项试验性横断面研究中,收集了42名接受富马酸二甲酯治疗的患者的数据,治疗剂量为240毫克,每天两次。在服药后 1-8 小时(中位数为 3 小时)或 10-14 小时(中位数为 13 小时)测定活性代谢物富马酸单甲酯的浓度。评估了富马酸单甲酯浓度与淋巴细胞绝对计数之间的关系:结果:富马酸单甲酯的浓度范围为 2.5-3177.9 μg/L,大多数浓度在服药后 10 小时左右检测不到。在给药后 1-8 小时(中位数为 3 小时)的亚组中,浓度/剂量比范围很广,从 0.04-6.62 不等。在淋巴细胞绝对计数组中,富马酸单甲酯的中位浓度为 0.04-6.62:富马酸单甲酯药代动力学的个体间差异很大,这可能是多发性硬化症患者对富马酸二甲酯反应不同的原因之一。在较高的血清富马酸单甲酯浓度与绝对淋巴细胞计数的关系中,观察到了一种不显著但明显的趋势。
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