**2. Pharmacokinetics of fumaric acid esters**

*Drug Repurposing - Hypothesis, Molecular Aspects and Therapeutic Applications*

multiple sclerosis.

from psoriasis, developed an interest in and isolated fumaric acid esters (FAE) from the plant extract. Excited about the positive effects of the FAE mixture on his own psoriatic lesions, he began offering it also to other psoriasis patients. Schweckendiek later published his findings on the beneficial effects of FAE in psoriasis [2], effects that he believed to be attributed to the improvements of this fumarate therapy on dysregulation of the citric acid cycle, the potential underlying cause of psoriasis. Nonetheless, with advancements in the understanding of psoriasis, his hypothesis was found to be incorrect. However, his preliminary observations laid the foundation for the successful development of a drug to treat psoriasis and interestingly,

In 1994, some three decades following Schweckendiek's initial report, a fumaric acid mixture composed in large (60%) of dimethyl fumarate (DMF) and ethyl hydrogen fumarates was authorized for the treatment of psoriasis in Germany under the brand name Fumaderm® [3]. In the clinical setting, Fumaderm® proved effective against moderate to severe forms of psoriasis. To date, it remains to be the most widely used oral compound for psoriasis therapy in Germany. However, Fumaderm® was not licensed and currently remains unlicensed for use in the UK and US [4]. Despite this, results establishing DMF to be the major active principle in the Fumaderm® led to numerous clinical and experimental studies worldwide on the immunomodulatory potential of Fumaderm® and DMF in other immune-mediated diseases [5, 6]. The extremely positive results that emanated from these studies led to DMF being tested clinically for the treatment of relapsing-remitting multiple sclerosis (RRMS). Like the original discovery of FAEs, the exploratory clinical trial of FAE for MS was performed in Germany [7]. In this trial, Fumaderm® was given to 10 patients with highly active RRMS; six patients completed the 70-week trial. Magnetic resonance imaging (MRI)-based results showed that Fumaderm® significantly reduced the number of gadolinium-enhanced lesions as well as lesion volumes without further worsening of any clinical parameters [7]. Although the overall safety profile of Fumaderm® was found to be favorable in this study, the associated unwanted gastrointestinal discomforts were a major concern. Although this initial study was a small, single-center, MRI-based and open-label clinical trial, it

set the stage for a number of subsequent MS trials with DMF.

referenced excellent reviews [12–17].

After Fumaderm® was licensed to be used in Germany, efforts to develop an improved formulation with better tolerability began. This culminated ultimately in the introduction of BG12 (brand name Tecfidera) a modified FAE formulation [8–10]. Indeed BG-12, comprised only of DMF made available in enteric-coated micro tablets, showed better gastrointestinal tolerability compared to Fumaderm® and following several clinical trials, this gastro-resistant, delayed-release formulation of DMF was ultimately approved for use in the United States, New Zealand and Australia for the treatment of relapsing forms and relapsing MS, respectively, and in the European Union, Switzerland and Canada for the treatment of RRMS [11]. A plethora of additional information exists on the use of DMF in the treatment of MS and psoriasis. For further reading on DMF and MS, please refer to the following

Drug repurposing is a highly appreciated strategy in the pharmaceutical industry [18]. The fact that agents have been previously tested prior testing of in humans and therefore a wealth of detailed information is already available regarding pharmacology, formulation and safety profile is a huge advantage! Such new candidate therapies can often be fast-tracked for clinical trials and related approval by the U.S. Food and Drug Administration. There is a burgeoning literature on the use of FAE in the prevention and treatment of diseases, other than psoriasis and MS,

**198**

Dimethyl fumarate (PubChem CID: 637568), described as a "white crystalline compound with a fruit-like taste" [19], is a dimethyl ester of fumaric acid with the official chemical name of trans-1,2-ethylene carboxylic acid dimethyl ester [20]. Because of its rapid degradation by intestinal esterase, DMF does not cross the intestinal wall in significant amounts [21]. Thus, because of its short-lived activity, evidence of direct, sustained anti-inflammatory or antioxidant effects derived directly from DMF is limited [22]. Instead, monomethyl fumarate (MMF; PubChem CID: 21721168), the product of DMF metabolism by intestinal esterase, is said to be the main active metabolite [23]. This is confirmed by pharmacokinetic studies that demonstrate following oral DMF intake, serum concentrations of MMF peak within 2–2.5 h and its half-life is approximately 1 h [24]. Further, the ingestion of DMF along with a high fat/high-calorie diet was found to interfere with intestinal absorption, delaying the systemic peak of MMF significantly [16, 17]. Following doses of delayed-release DMF of up to 240 mg, the mean Cmax of MMF in healthy human subjects was 1.43 μg/ml with a corresponding MMF area under the curve of 2.41 μg h/ml. There was no evidence of accumulation after multiple doses (e.g. 240 mg delayed-release DMF three times daily for 2 days) as MMF concentrations fell below detectable limits at the end of day 1 and day 2 [24]. MMF is eliminated primarily through breathing; negligible amounts of intact MMF are excreted through urine or feces. Additionally, there is no evidence of cytochrome P450-dependent metabolism of the compound in the liver [25]. Because of the lack of cytochrome P 450 involvement, DMF has very limited drug–drug interactions. Congruent with the above, both DMF and MMF have been popularly used for various pre-clinical pharmacological studies aimed at the testing and development of new therapeutics for various indications. The intestinal metabolism of DMF and diroximel fumarate (DRF), two current clinical FAE formulations is shown in **Figure 1**.

#### **Figure 1.**

*Metabolism of fumaric acid esters. Clinical formulations of FAE are composed of dimethyl fumarate (DMF) or diroximel fumarate (DRF). Following oral administration, intestinal esterase metabolizes both DMF and DRF into the major bioactive ingredient MMF (monomethyl fumarate). Methanol, hydroxyethyl succinimide (HES) and RDC-8439 are also produced but only as minor metabolites (< 10%).*
