Tecfidera - Clinical Pharmacology
Mechanism of Action
The mechanism by which dimethyl fumarate (DMF) exerts its therapeutic effect in multiple sclerosis is unknown. DMF and the metabolite, monomethyl fumarate (MMF), have been shown to activate the Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway in vitro and in vivo in animals and humans. The Nrf2 pathway is involved in the cellular response to oxidative stress. MMF has been identified as a nicotinic acid receptor agonist in vitro.

Pharmacodynamics
Potential to prolong the QT interval

In a placebo controlled thorough QT study performed in healthy subjects, there was no evidence that dimethyl fumarate caused QT interval prolongation of clinical significance (i.e., the upper bound of the 90% confidence interval for the largest placebo-adjusted, baseline-corrected QTc was below 10 ms).

Pharmacokinetics
After oral administration of Tecfidera, dimethyl fumarate undergoes rapid presystemic hydrolysis by esterases and is converted to its active metabolite, monomethyl fumarate (MMF). Dimethyl fumarate is not quantifiable in plasma following oral administration of Tecfidera. Therefore all pharmacokinetic analyses related to Tecfidera were performed with plasma MMF concentrations. Pharmacokinetic data were obtained in subjects with multiple sclerosis and healthy volunteers.

Absorption

The median Tmax of MMF is 2-2.5 hours. The peak plasma concentration (Cmax) and overall exposure (AUC) increased approximately dose proportionally in the dose range studied (120 mg to 360 mg). Following administration of Tecfidera 240 mg twice a day with food, the mean Cmax of MMF was 1.87 mg/L and AUC was 8.21 mg.hr/L in MS patients.

A high-fat, high-calorie meal did not affect the AUC of MMF but decreased its Cmax by 40%. The Tmax was delayed from 2.0 hours to 5.5 hours. In this study, the incidence of flushing was reduced by approximately 25% in the fed state.

Distribution

The apparent volume of distribution of MMF varies between 53 and 73 L in healthy subjects. Human plasma protein binding of MMF is 27-45% and independent of concentration.

Metabolism

In humans, dimethyl fumarate is extensively metabolized by esterases, which are ubiquitous in the gastrointestinal tract, blood, and tissues, before it reaches the systemic circulation. Further metabolism of MMF occurs through the tricarboxylic acid (TCA) cycle, with no involvement of the cytochrome P450 (CYP) system. MMF, fumaric and citric acid, and glucose are the major metabolites in plasma.

Elimination

Exhalation of CO2 is the primary route of elimination, accounting for approximately 60% of the Tecfidera dose. Renal and fecal elimination are minor routes of elimination, accounting for 16% and 1% of the dose respectively. Trace amounts of unchanged MMF were present in urine.

The terminal half-life of MMF is approximately 1 hour and no circulating MMF is present at 24 hours in the majority of individuals. Accumulation of MMF does not occur with multiple doses of Tecfidera.

Specific Populations

Body weight, gender, and age do not require dosage adjustment.

No studies have been conducted in subjects with hepatic or renal impairment. However, neither condition would