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CNS & Neurological Disorders - Drug Targets

Author(s): Zuzana Krska Kusnirikova, Ivana Kacirova, Veronika Pesakova, Pavel Hradilek, Hana Brozmanova and Milan Grundmann*

DOI: 10.2174/0118715273302279240529104919

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

Page: [1516 - 1523] Pages: 8

  • * (Excluding Mailing and Handling)

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.

[1]
Gold R, Kappos L, Arnold DL, et al. Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis. N Engl J Med 2012; 367(12): 1098-107.
[http://dx.doi.org/10.1056/NEJMoa1114287] [PMID: 22992073]
[2]
Fox RJ, Miller DH, Phillips JT, et al. Placebo-controlled phase 3 study of oral BG-12 or glatiramer in multiple sclerosis. N Engl J Med 2012; 367(12): 1087-97.
[http://dx.doi.org/10.1056/NEJMoa1206328] [PMID: 22992072]
[3]
Wu Q, Wang Q, Mao G, Dowling CA, Lundy SK, Mao-Draayer Y. Dimethyl fumarate selectively reduces memory t cells and shifts the balance between Th1/Th17 and Th2 in multiple sclerosis patients. J Immunol 2017; 198(8): 3069-80.
[http://dx.doi.org/10.4049/jimmunol.1601532] [PMID: 28258191]
[4]
Mehta D, Miller C, Arnold DL, et al. Effect of dimethyl fumarate on lymphocytes in RRMS. Neurology 2019; 92(15): e1724-38.
[http://dx.doi.org/10.1212/WNL.0000000000007262] [PMID: 30918100]
[5]
Galli E, Hartmann FJ, Schreiner B, et al. GM-CSF and CXCR4 define a T helper cell signature in multiple sclerosis. Nat Med 2019; 25(8): 1290-300.
[http://dx.doi.org/10.1038/s41591-019-0521-4] [PMID: 31332391]
[6]
Sheikh SI, Nestorov I, Russell H, et al. Tolerability and pharmacokinetics of delayed-release dimethyl fumarate administered with and without aspirin in healthy volunteers. Clin Ther 2013; 35(10): 1582-1594.e9.
[http://dx.doi.org/10.1016/j.clinthera.2013.08.009] [PMID: 24139424]
[7]
Tecfidera. https://www.ema.europa.eu/en/medicines/human/EPAR/tecfidera
[8]
Litjens NHR, Burggraaf J, Van Strijen E, et al. Pharmacokinetics of oral fumarates in healthy subjects. Br J Clin Pharmacol 2004; 58(4): 429-32.
[http://dx.doi.org/10.1111/j.1365-2125.2004.02145.x] [PMID: 15373936]
[9]
Edwards KR, Kamath A, Button J, et al. A pharmacokinetic and biomarker study of delayed-release dimethyl fumarate in subjects with secondary progressive multiple sclerosis: Evaluation of cerebrospinal fluid penetration and the effects on exploratory biomarkers. Mult Scler Relat Disord 2021; 51: 102861.
[http://dx.doi.org/10.1016/j.msard.2021.102861] [PMID: 33773271]
[10]
Linker RA, Gold R. Dimethyl fumarate for treatment of multiple sclerosis: Mechanism of action, effectiveness, and side effects. Curr Neurol Neurosci Rep 2013; 13(11): 394.
[http://dx.doi.org/10.1007/s11910-013-0394-8] [PMID: 24061646]
[11]
Sanchez VC, Carter JL. An evaluation of dimethyl fumarate for the treatment of relapsing remitting multiple sclerosis. Expert Opin Pharmacother 2020; 21(12): 1399-405.
[http://dx.doi.org/10.1080/14656566.2020.1763304] [PMID: 32543241]
[12]
Fox RJ, Chan A, Gold R, et al. Characterizing absolute lymphocyte count profiles in dimethyl fumarate–treated patients with MS. Neurol Clin Pract 2016; 6(3): 220-9.
[http://dx.doi.org/10.1212/CPJ.0000000000000238] [PMID: 27347439]
[13]
Rosenkranz T, Novas M, Terborg C. PML in a patient with lymphocytopenia treated with dimethyl fumarate. N Engl J Med 2015; 372(15): 1476-8.
[http://dx.doi.org/10.1056/NEJMc1415408] [PMID: 25853765]
[14]
Berger JR. Classifying PML risk with disease modifying therapies. Mult Scler Relat Disord 2017; 12: 59-63.
[http://dx.doi.org/10.1016/j.msard.2017.01.006] [PMID: 28283109]
[15]
Baharnoori M, Lyons J, Dastagir A, Koralnik I, Stankiewicz JM. Nonfatal PML in a patient with multiple sclerosis treated with dimethyl fumarate. Neurol Neuroimmunol Neuroinflamm 2016; 3(5): e274.
[http://dx.doi.org/10.1212/NXI.0000000000000274] [PMID: 27606353]
[16]
Russo DC, Scott KA, Pirmohamed M. Dimethyl fumarate induced lymphopenia in multiple sclerosis: A review of the literature. Pharmacol Ther 2021; 219: 107710.
[http://dx.doi.org/10.1016/j.pharmthera.2020.107710] [PMID: 33091427]
[17]
Birnbaum AK, Meador KJ, Karanam A, et al. Antiepileptic drug exposure in infants of breastfeeding mothers with epilepsy (MONEAD Investigator Group). JAMA Neurol 2020; 77(4): 441-50.
[http://dx.doi.org/10.1001/jamaneurol.2019.4443] [PMID: 31886825]
[18]
Keizer RJ, Jansen RS, Rosing H, et al. Incorporation of concentration data below the limit of quantification in population pharmacokinetic analyses. Pharmacol Res Perspect 2015; 3(2): e00131.
[http://dx.doi.org/10.1002/prp2.131] [PMID: 26038706]
[19]
Mrowietz U, Christophers E, Altmeyer P. Treatment of severe psoriasis with fumaric acid esters: Scientific background and guidelines for therapeutic use. Br J Dermatol 1999; 141(3): 424-9.
[http://dx.doi.org/10.1046/j.1365-2133.1999.03034.x] [PMID: 10584060]
[20]
Berger AA, Sottosanti ER, Winnick A, et al. Monomethyl fumarate (MMF, Bafiertam) for the treatment of relapsing forms of multiple sclerosis (MS). Neurol Int 2021; 13(2): 207-23.
[http://dx.doi.org/10.3390/neurolint13020022] [PMID: 34069538]
[21]
Jordan ALM, Yang J, Fisher CJ, Racke MK, Mao-Draayer Y. Progressive multifocal leukoencephalopathy in dimethyl fumarate-treated multiple sclerosis patients. Mult Scler 2022; 28(1): 7-15.
[http://dx.doi.org/10.1177/1352458520949158] [PMID: 32808554]
[22]
Ryerson LZ, Foley J, Chang I, et al. Risk of natalizumab-associated PML in patients with MS is reduced with extended interval dosing. Neurology 2019; 93(15): e1452-62.
[http://dx.doi.org/10.1212/WNL.0000000000008243] [PMID: 31515290]
[23]
van Kempen ZLE, Toorop AA, Sellebjerg F, Giovannoni G, Killestein J. Extended dosing of monoclonal antibodies in multiple sclerosis. Mult Scler 2022; 28(13): 2001-9.
[http://dx.doi.org/10.1177/13524585211065711] [PMID: 34949134]
[24]
Moccia M, Loperto I, Santoni L, et al. Healthcare resource utilization and costs for extended interval dosing of natalizumab in multiple sclerosis. Neurodegener Dis Manag 2022; 12(3): 109-16.
[http://dx.doi.org/10.2217/nmt-2021-0038] [PMID: 35446149]
[25]
Hauser SL, Bar-Or A, Comi G, et al. Ocrelizumab versus interferon beta-1a in relapsing multiple sclerosis. N Engl J Med 2017; 376(3): 221-34.
[http://dx.doi.org/10.1056/NEJMoa1601277] [PMID: 28002679]
[26]
Montalban X, Hauser SL, Kappos L, et al. Ocrelizumab versus placebo in primary progressive multiple sclerosis. N Engl J Med 2017; 376(3): 209-20.
[http://dx.doi.org/10.1056/NEJMoa1606468] [PMID: 28002688]
[27]
Hauser SL, Bar-Or A, Weber MS, et al. Association of higher ocrelizumab exposure with reduced disability progression in multiple sclerosis. Neurol Neuroimmunol Neuroinflamm 2023; 10(2): e200094.
[http://dx.doi.org/10.1212/NXI.0000000000200094] [PMID: 36792367]
[28]
European market concerns part 4 EU bans dimethyl fumarate. Available from: https://newsletter.sgs.com/eNewsletterPro/uploadedimages/000006/SGS-Safeguards-06409-EU-Bans-Dimethyl-Fumarate-in-Products-EN-09.pdf
[29]
Gold R, Arnold DL, Bar-Or A, et al. Long-term safety and efficacy of dimethyl fumarate for up to 13 years in patients with relapsing-remitting multiple sclerosis: Final ENDORSE study results. Mult Scler 2022; 28(5): 801-16.
[http://dx.doi.org/10.1177/13524585211037909] [PMID: 34465252]
[30]
Paolicelli D, Manni A, Iaffaldano A, Trojano M. Efficacy and safety of oral therapies for relapsing-remitting multiple sclerosis. CNS Drugs 2020; 34(1): 65-92.
[http://dx.doi.org/10.1007/s40263-019-00691-7] [PMID: 31898276]
[31]
Williams MJ, Amezcua L, Chinea A, et al. Real-world safety and effectiveness after 5 years of dimethyl fumarate treatment in black and hispanic patients with multiple sclerosis in ESTEEM. Neurol Ther 2023; 12(5): 1669-82.
[http://dx.doi.org/10.1007/s40120-023-00517-1] [PMID: 37354276]