Dimethyl fumarate

The anti-inflammatory and immunomodulating effects of dimethyl fumarate and its metabolite monomethyl fumarate are not fully elucidated but are thought to be mainly due to the interaction with the intracellular reduced glutathione of cells directly involved in the pathogenesis of psoriasis. This interaction with glutathione leads to the inhibition of translocation into the nucleus and the transcriptional activity of the nuclear factor kappa-light-chain-enhancer of activated B-cells (NF-κB).

The main activity of dimethyl fumarate and monomethyl fumarate is considered to be immunomodulatory, resulting in a shift in T helper cells (Th) from the Th1 and Th17 profile to a Th2 phenotype. The inflammatory cytokine production is reduced with induction of proapoptotic events, inhibition of keratinocyte proliferation, reduced expression of adhesion molecules, and diminished inflammatory infiltrate within psoriatic plaques.

Absorption

After oral administration, dimethyl fumarate is not detected in plasma because it is rapidly hydrolysed by esterases to its active metabolite monomethyl fumarate. After oral administration of a single 120 mg tablet in healthy subjects, monomethyl fumarate reached plasma peak concentrations of around 1325 ng/mL and 1311 ng/mL under fasted or fed conditions, respectively. Taking dimethyl fumarate with food delayed the t_max of monomethyl fumarate from 3.5 to 9.0 hours.

Distribution

The plasma protein binding of monomethyl fumarate is around 50%. Dimethyl fumarate does not show any binding affinity to serum proteins which may further contribute to its rapid elimination from the circulation. Biotransformation The biotransformation of dimethyl fumarate does not involve cytochrome P450 isoenzymes. In vitro studies have shown that monomethyl fumarate at the therapeutic dose does not inhibit or induce any of the cytochrome P450 enzymes, it is not a substrate or inhibitor of P-glycoprotein and is not an inhibitor of the most common efflux and uptake transporters. In vitro studies have shown that dimethyl fumarate at a therapeutic dose does not inhibit CYP3A4/5 and BCRP and is a weak P-glycoprotein inhibitor.

In vitro studies have shown that hydrolysis of dimethyl fumarate to monomethyl fumarate occurs rapidly at pH 8 (pH in the small intestine), but not at pH 1 (pH in the stomach). A part of the total dimethyl fumarate is hydrolysed by esterases and the alkaline milieu of the small intestine, while the remainder enters the portal vein blood. Further studies have shown that dimethyl fumarate (and to a lesser extent monomethyl fumarate) reacts partially with reduced glutathione forming a glutathioneadduct. These adducts were detected in animal studies in the intestinal mucosa of rats and to a smaller extent in portal vein blood. Unconjugated dimethyl fumarate, however, cannot be detected in the plasma of animals or psoriatic patients following oral administration. By contrast, unconjugated monomethyl fumarate is detectable in plasma. Further metabolism occurs through oxidation via the tricarboxylic acid cycle forming carbon dioxide and water.

Elimination

Exhalation of CO₂ resulting from the metabolism of monomethyl fumarate is the primary route of elimination; only small amounts of intact monomethyl fumarate are excreted through urine or faeces. The portion of dimethyl fumarate that reacts with glutathione, forming a glutathione-adduct, is metabolised further to its mercapturic acid, which is excreted in the urine.

The apparent terminal elimination half-life of monomethyl fumarate is about 2 hours.

Linearity/non-linearity

Despite the high inter-subject variability, the exposure measured as AUC and C_max was generally dose-proportional after single dose administration of 4 × 30 mg dimethyl fumarate tablets (total dose of 120 mg) and 2 × 120 mg dimethyl fumarate tablets (total dose of 240 mg).

Renal impairment

No specific studies have been performed in patients with renal impairment. However, because renal elimination plays a minor role in the total clearance from plasma, it is unlikely that renal impairment may affect the pharmacokinetic characteristics of dimethyl fumarate.

Hepatic impairment

No specific studies have been performed in patients with hepatic impairment. However, as dimethyl fumarate is metabolised by esterases and the alkaline milieu of the small intestine without the involvement of cytochrome P450, hepatic impairment is not expected to influence exposure.

Non-clinical safety pharmacology and genotoxicity data reveal no special hazard for humans.

Toxicology

The kidney was identified as a major target organ of toxicity in non-clinical studies. Renal findings in dogs included minimal to moderate tubular hypertrophy, increased incidence and severity of tubular vacuolation and minimal to slight tubular degeneration, which were considered toxicologically relevant. The no-observed adverse-effect-level (NOAEL) after 3 months of treatment was 30 mg/kg/day, which corresponds to 2.9-fold and 9.5-fold the human systemic exposure at the highest recommended dose (720 mg/day), as AUC and C_max values, respectively.

Reproduction toxicity

No fertility or pre- and post-natal development studies have been conducted with dimethyl fumarate.

There were no effects on foetal body weights or malformations attributed to maternal administration of dimethyl fumarate during the embryo-foetal development study in rats. However, there was an increased number of foetuses with the variations “supernumerary liver lobe” and “abnormal iliac alignment” at maternally toxic doses. The NOAEL for maternal and embryo-foetal toxicity was 40 mg/kg/day, corresponding to 0.2-fold and 2.0-fold the human systemic exposure at the highest recommended dose (720 mg/day), as AUC and C_max values, respectively.

Dimethyl fumarate has been shown to cross the placental membrane into foetal blood in rats.

Carcinogenicity

No carcinogenicity studies have been performed for dimethyl fumarate. Based on available data suggesting that fumaric acid esters may activate cellular pathways related to the development of renal tumours, a potential tumorigenic activity of exogenously administered dimethyl fumarate on the kidneys cannot be excluded.