Dimethyl Fumarate and Monoethyl Fumarate Exhibit Differential Pharmacodynamic Effects and Pharmacokinetics In Vivo (P1.207)
Bibliographic record
Abstract
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: Naïve 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.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".