4-O-[2-(2,5-dioxopyrrolidin-1-yl)ethyl] 1-O-methyl (E)-but-2-enedioate

Absorption

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.

Toxicity

Currently, an MSDS for diroximel fumarate is unavailable. The MSDS for its bioequivalent counterpart, dimethyl fumarate, indicates an oral LD50 of 2,240 mg/kg in rats.
There is no information regarding overdose on the FDA label for diroximel fumarate. Cases of overdose with its bioequivalent counterpart, dimethyl fumarate, have been reported in the literature, and symptoms reflect the adverse effects of this drug. These symptoms include nausea, vomiting, diarrhea, and flushing, among others. Currently there is no antidote to an overdose with diroximel fumarate or dimethyl fumarate. Symptomatic and supportive management are the only options up to this date if an overdose should occur.

Description

Diroximel fumarate is a prodrug form of monomethyl fumarate . It undergoes esterase cleavage in the gut to release monomethyl fumarate. Formulations containing diroximel fumarate have been used in the treatment of relapsing-remitting multiple sclerosis.

The Uses of 4-O-[2-(2,5-dioxopyrrolidin-1-yl)ethyl] 1-O-methyl (E)-but-2-enedioate

Diroximel Fumarate is a novel oral fumarate in development for the treatment of patients with relapsing forms of multiple sclerosis.

Background

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.

Indications

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.

Pharmacokinetics

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.

Metabolism

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.