Dimethyl Fumarate and Monoethyl Fumarate Exhibit Differential Pharmacodynamic Effects and Pharmacokinetics In Vivo (P1.207)

OBJECTIVE: To evaluate the pharmacodynamic effects and pharmacokinetics of dimethyl fumarate (DMF) and monoethyl fumarate (MEF) in vivo. BACKGROUND: Delayed-release DMF is approved in the U.S., Canada, and Australia for the treatment of multiple sclerosis. DMF is also one component of a combination product with 3 different salts of MEF, and this combination treatment is approved in Germany for psoriasis. Previous studies have characterized the in vivo properties of DMF; however MEF has been largely under explored. Characterizing potential common or distinct pharmacodynamic properties of DMF and MEF would provide important insights into the mechanisms of action for delayed-release DMF versus fixed combination products containing DMF and MEF salts. DESIGN/METHODS: Naive mice were dosed with DMF, MEF or a combination of the two. Pharmacodynamic responses and pharmacokinetics were evaluated after a single dose and after 10 days of repeated daily dosing in multiple peripheral and CNS tissues. RESULTS: Both DMF and MEF exhibited similar pharmacokinetic profiles, however differences were noted in biodistribution; monomethyl fumarate (MMF, the primary metabolite of DMF) exhibited a higher degree of brain penetration, whereas MEF was preferentially partitioned into kidney. Common pharmacodynamic responses were observed for DMF, MEF salts and combination treatment; however, unique responses for each treatment were also observed in all assessed tissues. Distinct pharmacodynamic responses were also observed with combination treatment, and these were not found with either individual component. CONCLUSIONS: DMF/MMF and MEF were absorbed to a similar degree after oral dosing, however there were biodistribution differences, most notably in brain and kidney. Both compounds alone or in combination were active in vivo, with some common responses and others distinct to each treatment. The data indicate that all fumaric acid esters cannot be each considered equivalent, and combinations of compounds may exert effects not observed when agents are used individually. Study Supported by: Biogen Idec Inc. Disclosure: Dr. Scannevin has received personal compensation for activities with Biogen Idec as an employee. Dr. Scannevin holds stock and/or stock options in Biogen Idec which sponsored research in which Dr. Scannevin was involved as an investigator. Dr. Szak has received personal compensation for activities with Biogen Idec as an employee. Dr. Szak holds stock and/or stock options in Biogen Idec stock, which sponsored research in which Dr. Szak was involved as an investigator. Dr. King has received personal compensation for activities with Biogen Idec. Dr. Brennan has received personal compensation for activities with Biogen Idec as an employee. Dr. Allaire has received personal compensation for activities with Biogen Idec as an employee. Dr. Allaire holds stock and/or stock options in Biogen Idec, which sponsored research in which Dr. Allaire was involved as an investigator. Dr Allaire holds stock and/or stock options in Biogen Idec. Dr. Cullen has received personal compensation for activities with Biogen Idec as an employee. Dr. Thai has received personal compensation for activities with Biogen Idec as an employee. Dr. Thomas has received personal compensation for activities with Biogen Idec as an employee. Dr. Gianni has received personal compensation for activities with Biogen Idec as an employee. Dr. Chou has received personal compensation for activities with Biogen Idec as an employee. Dr. Hillary has received personal compensation for activities with Biogen Idec as an employee. Dr. Wipke has received personal compensation for activities with Biogen Idec as an employee. Dr. Yang has received personal compensation for activities with Biogen Idec. Dr. Carulli has received personal compensation for activities with Biogen Idec as an employee. Dr. Huang has received personal compensation for activities with Biogen Idec as an employee. Dr. Rhodes has received personal compensation for activities with Biogen Idec as an employee. Dr. Rhodes has received research support from Biogen Idec.