Tolerability and Pharmacokinetics of Delayed-Release Dimethyl Fumarate Administered With and Without Aspirin in Healthy Volunteers

Sheikh, Sarah; Nestorov, Ivan; Russell, Heidy K.; O’Gorman, John; Ron, Huang; Milne, Ginger L.; Scannevin, Robert H.; Novas, Mark; Kp, Dawson

doi:10.1016/j.clinthera.2013.08.009

Cited by 51 publications

(48 citation statements)

References 21 publications

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“…One should recognize that the therapeutic response to DMF in MS is dose dependent (37), and it is possible that individual targets may vary in their sensitivity to different levels of MMF exposure. In this study, the plasma MMF levels obtained in DMF treatment of mice were severalfold higher than those in healthy volunteers treated with DMF doses used in MS (38). Of interest, when DMF was administered in vivo at a higher dose than was used in either our investigation of Nrf2-deficient mice or the study that evaluated HCAR2-deficient mice (35), it was observed that a majority of genes induced in spleen cells by DMF treatment were Nrf2 dependent (4).…”

Section: Discussionmentioning

confidence: 78%

Dimethyl fumarate treatment induces adaptive and innate immune modulation independent of Nrf2

Schulze-Topphoff

Varrin‐Doyer

Pekarek

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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260

213

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Dimethyl fumarate (DMF) (BG-12, Tecfidera) is a fumaric acid ester (FAE) that was advanced as a multiple sclerosis (MS) therapy largely for potential neuroprotection as it was recognized that FAEs are capable of activating the antioxidative transcription factor nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway. However, DMF treatment in randomized controlled MS trials was associated with marked reductions in relapse rate and development of active brain MRI lesions, measures considered to reflect CNS inflammation. Here, we investigated the antiinflammatory contribution of Nrf2 in DMF treatment of the MS model, experimental autoimmune encephalomyelitis (EAE). C57BL/6 wild-type (WT) and Nrf2-deficient (Nrf2 −/− ) mice were immunized with myelin oligodendrocyte glycoprotein (MOG) peptide 35-55 (p35-55) for EAE induction and treated with oral DMF or vehicle daily. DMF protected WT and Nrf2 −/− mice equally well from development of clinical and histologic EAE. The beneficial effect of DMF treatment in Nrf2 −/− and WT mice was accompanied by reduced frequencies of IFN-γ and IL-17-producing CD4 + cells and induction of antiinflammatory M2 (type II) monocytes. DMF also modulated B-cell MHC II expression and reduced the incidence of clinical disease in a B-cell-dependent model of spontaneous CNS autoimmunity. Our observations that oral DMF treatment promoted immune modulation and provided equal clinical benefit in acute EAE in Nrf2 −/− and WT mice, suggest that the antiinflammatory activity of DMF in treatment of MS patients may occur through alternative pathways, independent of Nrf2.multiple sclerosis | dimethyl fumarate | Nrf2 | EAE | M2 monocytes

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Section: Discussionmentioning

confidence: 78%

Dimethyl fumarate treatment induces adaptive and innate immune modulation independent of Nrf2

Schulze-Topphoff

Varrin‐Doyer

Pekarek

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

260

213

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“…treatment produces therapeutic MMF plasma levels in SCD mice. In the clinic, DMF is rapidly converted to MMF, which is its major bioactive metabolite (30). In a nonclinical study, DMF delivered to the small intestine of anesthetized rats resulted in the peak plasma levels of MMF within 9-15 minutes (31).…”

Section: Dmf and Mmf Induce Hbf In Erythroid Progenitors Generated Frmentioning

confidence: 99%

Dimethyl fumarate increases fetal hemoglobin, provides heme detoxification, and corrects anemia in sickle cell disease

Krishnamoorthy¹,

Pace²,

Gupta³

et al. 2017

JCI Insight

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“…Elevated levels of prostaglandin D2 in some DMF-treated individuals suggested that flushing may be, at least in part, prostaglandin mediated [Sheikh et al 2013]. In countries where the FDA-approved dosage of 325 mg ASS is not available, lower dosages such as 200 mg ASS may be used.…”

Section: Safety and Tolerability Issues With Dimethyl Fumarate In CLImentioning

confidence: 99%

Dimethyl fumarate in multiple sclerosis: latest developments, evidence and place in therapy

Linker

Haghikia

2016

Therapeutic Advances in Chronic Disease

114

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Dimethyl fumarate (DMF) is one of the newer additions to the armamentarium of potent immunomodulators for the treatment of relapsing-remitting multiple sclerosis (RRMS). After more than 2 years of real-world experience and more than 190,000 patients currently treated with DMF worldwide, it is a good timepoint to review the experience gathered so far and to re-evaluate the potential of this first-line oral multiple sclerosis (MS) drug. Post-hoc analyses of clinical and magnetic resonance imaging (MRI) data, some comprising more than 6 years of drug exposure including patients from the clinical trials, and the overall notion in clinical practice widely confirm the good efficacy of DMF in RRMS. Despite an overall good safety profile, it became also clear that the necessary clinical vigilance while using DMF may not be neglected. So far, four reported cases of progressive multifocal leukoencephalopathy (PML), a towering shadow over many MS therapies, warrant proper attention in newly-updated risk management plans. This review recapitulates efficacy and safety aspects of DMF therapy in relation to reported data from the pivotal clinical trials. In addition, we summarize recent insights into DMF mechanisms of action drawn from the field of basic research which may have important implications for clinical practice.

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Tolerability and Pharmacokinetics of Delayed-Release Dimethyl Fumarate Administered With and Without Aspirin in Healthy Volunteers

Cited by 51 publications

References 21 publications

Dimethyl fumarate treatment induces adaptive and innate immune modulation independent of Nrf2

Dimethyl fumarate treatment induces adaptive and innate immune modulation independent of Nrf2

Dimethyl fumarate increases fetal hemoglobin, provides heme detoxification, and corrects anemia in sickle cell disease

Dimethyl fumarate in multiple sclerosis: latest developments, evidence and place in therapy

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