Pharmacokinetics of oral fumarates in healthy subjects

Abstract

AimsTo characterize the pharmacokinetics of fumarates in healthy subjects. MethodsTen subjects received a single fumarate tablet (containing 120 mg of dimethylfumarate and 95 mg of calcium-monoethylfumarate) in the fasted state and after a standardized breakfast in randomized order. Prior to and at fixed intervals after the dose, blood samples were drawn and the concentrations of monomethylfumarate, the biologically active metabolite, as well as dimethylfumarate and fumaric acid were measured using high-performance liquid chromatography. ResultsAfter a lag time, a transient increase in serum monomethylfumarate concentrations in the blood was observed, whereas dimethylfumarate and fumaric acid concentrations remained below the detection limit. The t lag was 240 min [range 60-603 min; 95% confidence interval (CI) 139, 471] shorter when the tablet was taken after an overnight fast (90 min; range 60-120 min; 95% CI 66, 107) than when taken with breakfast (300 min; range 180-723 min; 95% CI 0, 1002). The t max was 241 min (range 60-1189 min, 95% CI 53, 781) shorter when the tablet was taken after an overnight fast (182 min; range 120-240 min; 95% CI 146, 211) than when taken with breakfast (361 min; range 240-1429 min; 95% CI 0, 1062). The mean C max for monomethylfumarate in the blood of fasting subjects was to 0.84 mg l -1 (range 0.37-1.29 mg l -1 ; 95% CI 0.52, 1.07) and did not differ from that in fed subjects (0.48 mg l -1 ; range 0-1.22 mg l -1 ; 95% CI 0, 5.55). ConclusionsThe pharmacokinetics of monomethylfumarate in healthy subjects after a single tablet of fumarate are highly variable, particularly after food intake. Further experiments exploring the pharmacokinetics of oral fumarates are warranted in order to elucidate the mechanisms underlying variability in reponse in patients.

The Antipsoriatic Agent Monomethylfumarate Has Antiproliferative, Prodifferentiative, and Anti-Inflammatory Effects on Keratinocytes

“…However, DMF does not seem to be the bioactive ingredient because it is not detected in patients' blood for a sufficient length of time to be exerting an action on its own (Litjens et al, 2004a). Furthermore, according to previous clinical and experimental studies, most of the DMF is hydrolyzed to MMF, which, in turn, is thought to act as an antipsoriatic agent (Rostami Yazdi and Mrowietz, 2008;Rostami-Yazdi et al, 2009).…”

Fumaric Acid Esters as Potential Therapies for Treating Degenerative Retinal Disease

“…MMF treatment was associated with significant increases in the expression of Nrf2-responsive antioxidant genes and a suppression of inflammatory responses as evidenced by increased expression of NAD(P)H quinone dehydrogenase 1, thioredoxin reductase 1 and hemeoxygenase-1 along with decrease in interlukin-1β, chemokine (C-C motif) ligand expressions [2,7,12]. Collectively, these molecular improvements interpreted to improve retinal function as evidenced by electroretinogram recordings performed on live mice.…”

“…Immediately after oral intake, DMF is acted upon by intestinal esterases to form Monomethyl Fumarate (MMF); hence, MMF is the primary bioactive ingredient [6]. Following DMF ingestion, circulating MMF concentrations peak between 2-2.5 hrs and the half-life of the metabolite is around 12 hrs [7]. Recent studies have reported the use and potential efficacy of MMF in the treatment of various diseases other than those named above.…”

Dimethyl fumarate: a new oral treatment option for multiple sclerosis

“…33 Therefore patients taking DMF should have a complete blood count (CBC) before starting treatment to measure lymphocyte count and an annual follow up CBC investigation.…”