Absorption, Distribution and Excretion
Diroximel fumarate is rapidly absorbed in the gastrointestinal tract following administration, like its bioequivalent drug, dimethyl fumarate. The median Tmax of monomethyl fumarate (MMF) after oral administration ranges from 2.5-3 hours with a mean Cmax of 2.11 mg/L. The bioequivalent drug, dimethyl fumarate, administered to healthy volunteers also shows a similar mean Tmax and Cmax. The average steady state concentration of this metabolite is estimated at 8.32 mg.hr/L after it is administered twice a day in patients with MS. The mean AUC0–∞ of the active metabolite is 88mg × min L−1. Food appears to significantly reduce the Cmax of diroximel fumarate's active metabolite, MMF, when compared to administration in the fasted state.
Monomethyl fumarate is eliminated as carbon dioxide through expired breath. Negligible amounts, under 0.3% of the ingested dose, are measured in urine. The inactive metabolite, 2-hydroxyethyl succinimide (HES), representing 58-63% of the ingested dose, is excreted in urine.
The apparent volume of distribution ranges from 72L to 83L. Monomethyl fumarate (MMF), the active metabolite of diroximel fumarate, crosses the blood brain barrier.
No clearance information is available on the FDA label for diroximel fumarate, however, clinical study results for its active metabolite, monomethyl fumarate show a mean apparent total clearance from the plasma after oral administration of 1.54 mgL−1.

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Metabolism / Metabolites
Esterases heavily metabolize diroximel fumarate, as well as its bioequivalent drug, dimethyl fumarate, in the liver. These enzymes are present in high quantities in the gastrointestinal tract, tissues, and blood. Esterase metabolism of this drug produces the active metabolite, mono methyl fumarate (MMF), before it moves to the systemic circulation. In addition, the major inactive metabolite, 2-hydroxyethyl succinimide (HES) is produced along with small amounts of methanol, and another inactive metabolite, RDC-8439. Following esterase metabolism, the tricarboxylic acid (TCA)cycle further metabolizes MMF. The major metabolites of MMF in plasma include fumaric acid, citric acid, and glucose. It is important that methanol is a major metabolite of dimethyl fumarate metabolism, but a minor metabolite of diroximel fumarate metabolism, conferring its lower risk of gastrointestinal effects.

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Biological Half-Life
The terminal half-life of monomethyl fumarate (MMF), diroximel fumarate's active metabolite, is estimated to be 1 hour.

Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
No information is available on the clinical use of diroximel fumarate during breastfeeding. However, amounts of the active metabolite of diroximel fumarate, monomethyl fumarate, in breastmilk appear to be low and would not be expected to cause any adverse effects in breastfed infants. Based on clinical data in over 20 infants exposed to dimethyl fumarate in breastmilk, diroximel fumarate is acceptable to use during breastfeeding, at least after one month of age. Breastfed infants should be monitored for adequate weight gain, and developmental milestones, especially in younger, exclusively breastfed infants. Some authors also recommend monitoring breastfed infants for flushing, vomiting and diarrhea.
◉ Effects in Breastfed Infants
Twenty-six women taking dimethyl fumarate for relapsing-remitting multiple sclerosis were followed during 29 pregnancies from 2015 to 2020. Dimethyl fumarate was administered through week 24 of pregnancy and resumed 1 month after delivery. Twenty-two of 26 mothers breastfed (extent not stated) for 4 to 7 months. Infants were monitored up to the third year of life for infections and developmental disorders. All children were the 70th and 95th percentile for height and weight. The authors concluded that continuing dimethyl fumarate while breastfeeding is safe, although infants were not exposed during the first month of life.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

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Protein Binding
Plasma protein binding of MMF, the active metabolite of diroximel fumarate, ranges from 27-45%.

:https://multiplesclerosisnewstoday.com/2019/02/27/fda-review-nda-diroximel-fumarate-relapsing-forms-ms/

Multiple Sclerosis (MS) is a chronic, debilitating neurological disease that can lead to profound cognitive and physical symptoms, severely affecting quality of life. It is the main cause of neurological disability not caused by trauma in the young adult population of both North America and Europe. Relapsing-remitting forms of MS lead to neurological symptoms that resolve and recur periodically. More than 80% of patients suffering from this disease have relapsing-remitting MS. Diroximel fumarate is a new drug from the fumarate class formulated to treat various relapsing forms of MS. This drug is bioequivalent to [Dimethyl fumarate](initially manufactured in 2013), but is less likely to cause gastrointestinal side effects, owing to its unique chemical structure. Diroximel fumarate was formulated by Alkermes in collaboration with Biogen, and was approved by the FDA in October 2019 and by the EMA in November 2021.
See also: Monomethyl Fumarate (has active moiety).

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Drug Indication
Diroximel fumarate is indicated for the treatment of relapsing forms of multiple sclerosis (MS) in adults; specifically active secondary progressive disease and clinically isolated syndrome, as well as relapsing-remitting MS.
Vumerity is indicated for the treatment of adult patients with relapsing remitting multiple sclerosis (see Section 5. 1 for important information on the populations for which efficacy has been established).

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Mechanism of Action
Currently, the mechanism of action of this drug in MS is not fully understood. Diroximel fumarate is hypothesized to regulate cell signaling pathways, causing beneficial immune and neuroprotective effects. Monomethyl fumarate (MMF) is the active metabolite of diroximel fumarate, and activates the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway in humans. This pathway occurs as a response to oxidative stress in cells. In addition to the above, MMF is a nicotinic acid receptor agonist in the laboratory setting. The relevance of this finding to the treatment of MS is unknown at this time. The mechanism by which this drug leads to less gastrointestinal effects is purported to be due to its lack of a methanol leaving group in its chemical structure, and substitution with inert 2-hydroxyethyl succinimide.

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Pharmacodynamics
Diroximel fumarate relieves the neurological symptoms of relapsing MS with less gastrointestinal effects than its bioequivalent counterpart, dimethyl fumarate. It is important to note that diroximel fumarate can cause angioedema, anaphylaxis, hepatotoxicity, flushing, lymphopenia, and Progressive Multifocal Leukoencephalopathy (PML). Discontinue diroximel fumarate immediately if PML is suspected or if anaphylaxis or angioedema occur. Liver function and total bilirubin should be tested prior to initiating diroximel fumarate and during treatment. A complete blood count (CBC) should be obtained prior to starting diroximel fumarate, after the first 6 months of administration, and at subsequent intervals of 6 to 12 months following this period. Suspend treatment if lymphocyte counts are measured to be less than 0.5 × 109/L for more than 6 months.

C11H13NO6

255.224023580551

255.074

1577222-14-0

73330464

White to off-white solid powder

1.3±0.1 g/cm3

441.0±25.0 °C at 760 mmHg

102-106

220.5±23.2 °C

0.0±1.1 mmHg at 25°C

1.515

-0.24

0

6

7

18

384

0

COC(=O)/C=C/C(=O)OCCN1C(=O)CCC1=O

YIMYDTCOUQIDMT-SNAWJCMRSA-N

InChI=1S/C11H13NO6/c1-17-10(15)4-5-11(16)18-7-6-12-8(13)2-3-9(12)14/h4-5H,2-3,6-7H2,1H3/b5-4+

2-(2,5-dioxopyrrolidin-1-yl)ethyl methyl fumarate

ALKS-8700; BIIB-098; VUMERITY™; ALKS8700; ALKS 8700; ALKS-8700

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~125 mg/mL (~489.77 mM)
H2O : ≥ 10 mg/mL (~39.18 mM)

Solubility in Formulation 1: 2.08 mg/mL (8.15 mM) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.08 mg/mL (8.15 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.08 mg/mL (8.15 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)